Mono-and disubstituted 3-propyl gamma-aminobutyric acids

ABSTRACT

The instant invention is a series of novel mono- and disubstituted 3-propyl gamma aminobutyric acids of Formula I  
                 
 
     The compounds are useful as therapeutic agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, arthritis, sleep disorders, IBS, and gastric damage. Methods of preparing the compounds and useful intermediates are also part of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.10/324,929 filed Dec. 20, 2002, which is a continuation of U.S.application Ser. No. 10/009,938 filed Dec. 10, 2001, which is a 371filing of PCT/US00/15070 filed May 31, 2000, which claims the benefit ofU.S. Provisional Application 60/138,485 filed Jun. 10, 1999; the entirecontents of which applications are hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] Compounds of formula

[0003] wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or6 are known in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

[0004] Compounds of formula

[0005] or a pharmaceutically acceptable salt thereof wherein R₁ is astraight or branched alkyl group having from 1 to 6 carbon atoms, phenylor cycloalkyl having from 3 to 6 carbon atoms; R₂ is hydrogen or methyl;and R₃ is hydrogen, or carboxyl are known in U.S. Pat. No. 5,563,175 andits various divisionals. These patents are hereby incorporated byreference.

SUMMARY OF THE INVENTION

[0006] The compounds of the instant invention are those of Formula I

[0007] or a pharmaceutically acceptable salt thereof wherein:

[0008] R¹ is hydrogen, straight or branched alkyl of from 1 to 6 carbonatoms or phenyl;

[0009] R² is straight or branched alkyl of from 1 to 8 carbon atoms,

[0010] straight or branched alkenyl of from 2 to 8 carbon atoms,

[0011] cycloalkyl of from 3 to 7 carbon atoms,

[0012] alkoxy of from 1 to 6 carbon atoms,

[0013] alkylcycloalkyl,

[0014] alkylalkoxy,

[0015] alkyl OH

[0016] alkylphenyl,

[0017] alkylphenoxy,

[0018] phenyl or substituted phenyl; and

[0019] R¹ is straight or branched alkyl of from 1 to 6 carbon atoms orphenyl when R² is methyl.

[0020] Preferred compounds are those of Formula I wherein R¹ ishydrogen, and R² is alkyl.

[0021] Other preferred compounds are those of Formula I wherein R¹ ismethyl, and R² is alkyl.

[0022] Still other preferred compounds are those of Formula I wherein R¹is methyl, and R² is methyl or ethyl.

[0023] Especially preferred compounds are selected from:

[0024] 3-Aminomethyl-5-methylheptanoic acid;

[0025] 3-Aminomethyl-5-methyl-octanoic acid;

[0026] 3-Aminomethyl-5-methyl-nonanoic acid;

[0027] 3-Aminomethyl-5-methyl-decanoic acid;

[0028] 3-Aminomethyl-5-methyl-undecanoic acid;

[0029] 3-Aminomethyl-5-methyl-dodecanoic acid;

[0030] 3-Aminomethyl-5-methyl-tridecanoic acid;

[0031] 3-Aminomethyl-5-cyclopropyl-hexanoic acid;

[0032] 3-Aminomethyl-5-cyclobutyl-hexanoic acid;

[0033] 3-Aminomethyl-5-cyclopentyl-hexanoic acid;

[0034] 3-Aminomethyl-5-cyclohexyl-hexanoic acid;

[0035] 3-Aminomethyl-5-trifluoromethyl-hexanoic acid;

[0036] 3-Aminomethyl-5-phenyl-hexanoic acid;

[0037] 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid;

[0038] 3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid;

[0039] 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid;

[0040] 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid;

[0041] 3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid;

[0042] 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and

[0043] 3-Aminomethyl-5-(phenylmethyl)-hexanoic acid.

[0044] Other especially preferred compounds are selected from:

[0045] (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid;

[0046] 3-Aminomethyl-4,5-dimethyl-hexanoic acid;

[0047] (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;

[0048] (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid;

[0049] (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;

[0050] 3-Aminomethyl-4-isopropyl-hexanoic acid;

[0051] 3-Aminomethyl-4-isopropyl-heptanoic acid;

[0052] 3-Aminomethyl-4-isopropyl-octanoic acid;

[0053] 3-Aminomethyl-4-isopropyl-nonanoic acid;

[0054] 3-Aminomethyl-4-isopropyl-decanoic acid; and

[0055] 3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid.

[0056] Other preferred compounds are selected from

[0057] (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid;

[0058] (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid;

[0059] (3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid;

[0060] (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid;

[0061] (3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid;

[0062] (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid;

[0063] (3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid;

[0064] (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid;

[0065] (3S,5S)-3-Am inomethyl-5-phenoxy-hexanoic acid;

[0066] (3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid;

[0067] (3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid;

[0068] (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid;

[0069] (3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid;

[0070] (3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid;

[0071] (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid;

[0072] (3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid;

[0073] (3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid;

[0074] (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;

[0075] (3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid;

[0076] (3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid;

[0077] (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid;

[0078] (3S,5S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;

[0079] (3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;

[0080] (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

[0081] (3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;

[0082] (3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

[0083] (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

[0084] (3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

[0085] (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid;

[0086](3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoicacid;

[0087] (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

[0088] (3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoicacid;

[0089] (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoicacid;

[0090] (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoicacid;

[0091] (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoicacid;

[0092] (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoicacid;

[0093] (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoicacid;

[0094] (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoicacid;

[0095] (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoicacid;

[0096] (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoicacid;

[0097] (3S,5S)-3-Aminomethyl-5-methyl6-(4-trifluoromethyl-phenoxy)-hexanoic acid;

[0098] (3S,5S)-3-Aminomethyl-5-methyl6-(3-trifluoromethyl-phenoxy)-hexanoic acid;

[0099] (3S,5S)-3-Aminomethyl-5-methyl6-(2-trifluoromethyl-phenoxy)-hexanoic acid;

[0100] (3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;

[0101] (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid;

[0102] (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid;

[0103] (3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

[0104] (3S,5S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

[0105] (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;

[0106] (3S,5S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

[0107] (3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;

[0108] (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

[0109] (3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

[0110] (3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

[0111] (3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoicacid;

[0112](3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoicacid;

[0113] (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

[0114] (3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

[0115] (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoicacid;

[0116] (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoicacid;

[0117] (3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoicacid;

[0118] (3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoicacid;

[0119] (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoicacid;

[0120] (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoicacid;

[0121] (3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0122] (3S,5S)-3-Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0123] (3S,5S)-3-Aminomethyl-7-(2-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0124](3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoicacid;

[0125](3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoicacid;

[0126](3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoicacid;

[0127] (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoicacid;

[0128] (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoicacid;

[0129] (3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoicacid;

[0130] (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;

[0131] (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid;

[0132] (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;

[0133] (3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid;

[0134] (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoicacid;

[0135] (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoicacid;

[0136] (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoicacid;

[0137] (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid;

[0138] (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;

[0139] (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid;

[0140] (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;

[0141] (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoicacid;

[0142] (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoicacid;

[0143] (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoicacid;

[0144] (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoicacid;

[0145] (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoicacid;

[0146] (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoicacid;

[0147] (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoicacid;

[0148] (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoicacid;

[0149] (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoicacid;

[0150] (3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid;

[0151] (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid;

[0152] (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0153] (Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0154] (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0155] (E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0156] (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0157] (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0158] (Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid;

[0159] (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid;

[0160] (3S,5S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;

[0161] (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid;

[0162] (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid;

[0163] (3S,5S)-3-Aminomethyl-5-cyclobutyl-hexanoic acid;

[0164] (3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; and

[0165] (3S,5S)-3-Aminomethyl-5-cyclohexyl-hexanoic acid.

[0166] Still other more preferred compounds are:

[0167] (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;

[0168] (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid;

[0169] (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid;

[0170] (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid;

[0171] (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid;

[0172] (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid;

[0173] (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid;

[0174] (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid;

[0175] (3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid;

[0176] (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

[0177] (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

[0178] (3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

[0179] (3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

[0180] (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

[0181] (3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

[0182] (3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

[0183] (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

[0184] (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

[0185] (3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

[0186] (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

[0187] (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

[0188] (3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

[0189] (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

[0190] (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

[0191] (3S,5R)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;

[0192] (3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;

[0193] (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;

[0194] (3S,5R)-3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;

[0195] (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; and

[0196] (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid.

[0197] The invention is also a pharmaceutical composition comprising atherapeutically effective amount of one or more compounds of Formula Iand a pharmaceutically acceptable carrier.

[0198] The compounds of the invention are useful in the treatment ofepilepsy, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, depression, anxiety, panic, pain,neuropathological disorders, arthritis, sleep disorders, irritable bowelsyndrome (IBS), and gastric damage.

DETAILED DESCRIPTION OF THE INVENTION

[0199] The compounds of the instant invention are mono- anddisubstituted 3-propyl gamma-aminobutyric acids as shown in Formula Iabove.

[0200] The terms are as described below or as they occur in thespecification.

[0201] The term alkyl or alkenyl is a straight or branched group of from1 to 8 carbon atoms or 2 to 8 carbon atoms including but not limited tomethyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl,and octyl. Alkyl can be unsubstituted or substituted by from 1 to 3fluorine atoms. Preferred groups are methyl and ethyl.

[0202] Cycloalkyl is a cyclic group of from 3 to 7 carbon atoms.

[0203] The benzyl and phenyl groups may be unsubstituted or substitutedwith from 1 to 3 groups each independents selected from halogen,especially fluoro, alkoxy, alkyl, and amino.

[0204] Halogen includes fluorine, chlorine, bromine, and iodine.

[0205] Alkoxy is as described above for alkyl.

[0206] Since amino acids are amphoteric, pharmacologically compatiblesalts when R is hydrogen can be salts of appropriate inorganic ororganic acids, for example, hydrochloric, sulphuric, phosphoric, acetic,oxalic, lactic, citric, malic, salicylic, malonic, maleic, succinic, andascorbic. Starting from corresponding hydroxides or carbonates, saltswith alkali metals or alkaline earth metals, for example, sodium,potassium, magnesium, or calcium are formed. Salts with quaternaryammonium ions can also be prepared with, for example, thetetramethyl-ammonium ion.

[0207] Prodrugs of compounds I-VIII are included in the scope of theinstant invention. Aminoacyl-glycolic and -lactic esters are known asprodrugs of amino acids (Wermuth C. G., Chemistry and Industry,1980:433-435). The carbonyl group of the amino acids can be esterifiedby known means. Prodrugs and soft drugs are known in the art (PalominoE., Drugs of the Future, 1990;15(4):361-368). The last two citations arehereby incorporated by reference.

[0208] The effectiveness of an orally administered drug is dependentupon the drug's efficient transport across the mucosal epithelium andits stability in entero-hepatic circulation. Drugs that are effectiveafter parenteral administration but less effective orally, or whoseplasma half-life is considered too short, may be chemically modifiedinto a prodrug form.

[0209] A prodrug is a drug which has been chemically modified and may bebiologically inactive at its site of action, but which may be degradedor modified by one or more enzymatic or other in vivo processes to theparent bioactive form.

[0210] This chemically modified drug, or prodrug, should have adifferent pharmacokinetic profile to the parent, enabling easierabsorption across the mucosal epithelium, better salt formulation and/orsolubility, improved systemic stability (for an increase in plasmahalf-life, for example). These chemical modifications may be

[0211] 1) ester or amide derivatives which may be cleaved by, forexample, esterases or lipases. For ester derivatives, the ester isderived from the carboxylic acid moiety of the drug molecule by knownmeans. For amide derivatives, the amide may be derived from thecarboxylic acid moiety or the amine moiety of the drug molecule by knownmeans.

[0212] 2) peptides which may be recognized by specific or nonspecificproteinases. A peptide may be coupled to the drug molecule via amidebond formation with the amine or carboxylic acid moiety of the drugmolecule by known means.

[0213] 3) derivatives that accumulate at a site of action throughmembrane selection of a prodrug form or modified prodrug form,

[0214] 4) any combination of 1 to 3.

[0215] Current research in animal experiments has shown that the oralabsorption of certain drugs may be increased by the preparation of“soft” quaternary salts. The quaternary salt is termed a “soft”quaternary salt since, unlike normal quaternary salts, e.g., R—N⁺(CH₃)₃,it can release the active drug on hydrolysis.

[0216] “Soft” quaternary salts have useful physical properties comparedwith the basic drug or its salts. Water solubility may be increasedcompared with other salts, such as the hydrochloride, but more importantthere may be an increased absorption of the drug from the intestine.Increased absorption is probably due to the fact that the “soft”quaternary salt has surfactant properties and is capable of formingmicelles and unionized ion pairs with bile acids, etc., which are ableto penetrate the intestinal epithelium more effectively. The prodrug,after absorption, is rapidly hydrolyzed with release of the activeparent drug.

[0217] Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

[0218] The compounds of the present invention includes all enantiomericand epimeric forms as well as the appropriate mixtures thereof. Forexample, the compound of Example 1 is a mixture of all four possiblestereoisomers. The compound of Example 6 is one of the isomers. Theconfiguration of the cyclohexane ring carbon centers may be R or S inthese compounds where a configuration can be defined.

[0219] The radioligand binding assay using [³H]gabapentin and the α₂δsubunit derived from porcine brain tissue was used (Gee N. S., Brown J.P., Dissanayake V. U. K., Offord J., Thurlow R., Woodruff G. N., “TheNovel Anti-convulsant Drug, Gabapentin, Binds to the α₂δ Subunit of aCalcium Channel,” J. Biol. Chem., 1996;271:5879-5776). TABLE 1 [³H] GBPAnticonvulsant Binding % Protect Structure (IC₅₀, nM) 1 hr 2 hr

0.218 100

1.8 0 0

0.04 80 100

0.206 0 20

On test 0 20

0.092 60 100

[0220] Table 1 above shows the binding affinity of the compounds of theinvention to the α₂δ subunit.

[0221] The compounds of the invention are compared to Neurontin®, amarketed drug effective in the treatment of such disorders as epilepsy.Neurontin® is 1-(aminomethyl)-cyclohexaneacetic acid of structuralformula

[0222] Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in this assay.The compounds of the instant invention are expected, therefore, toexhibit pharmacologic properties comparable to or better thangabapentin. For example, as agents for convulsions, anxiety, and pain.

[0223] The present invention also relates to therapeutic use of thecompounds of the mimetic as agents for neurodegenerative disorders.

[0224] Such neurodegenerative disorders are, for example, Alzheimer'sdisease, Huntington's disease, Parkinson's disease, and AmyotrophicLateral Sclerosis.

[0225] The present invention also covers treating neurodegenerativedisorders termed acute brain injury. These include but are not limitedto: stroke, head trauma, and asphyxia.

[0226] Stroke refers to a cerebral vascular disease and may also bereferred to as a cerebral vascular incident (CVA) and includes acutethromboembolic stroke. Stroke includes both focal and global ischemia.Also, included are transient cerebral ischemic attacks and othercerebral vascular problems accompanied by cerebral ischemia. A patientundergoing carotid endarterectomy specifically or other cerebrovascularor vascular surgical procedures in general, or diagnostic vascularprocedures including cerebral angiography and the like.

[0227] Other incidents are head trauma, spinal cord trauma, or injuryfrom general anoxia, hypoxia, hypoglycemia, hypotension as well assimilar injuries seen during procedures from embole, hyperfusion, andhypoxia.

[0228] The instant invention would be useful in a range of incidents,for example, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

[0229] Pain refers to acute as well as chronic pain.

[0230] Acute pain is usually short-lived and is associated withhyperactivity of the sympathetic nervous system. Examples arepostoperative pain and allodynia.

[0231] Chronic pain is usually defined as pain persisting from 3 to 6months and includes somatogenic pains and psychogenic pains. Other painis nociceptive.

[0232] Still other pain is caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

[0233] Psychogenic pain is that which occurs without an organic originsuch as low back pain, a typical facial pain, and chronic headache.

[0234] Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, andother forms of neuralgia, neuropathic and idiopathic pain syndrome.

[0235] A skilled physician will be able to determine the appropriatesituation in which subjects are susceptible to or at risk of, forexample, stroke as well as suffering from stroke for administration bymethods of the present invention.

[0236] The compounds of the invention are also expected to be useful inthe treatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

[0237] GABA is an inhibitory neurotransmitter with the central nervoussystem. Within the general context of inhibition, it seems likely thatGABA-mimetics might decrease or inhibit cerebral function and mighttherefore slow function and decrease mood leading to depression.

[0238] The compounds of the instant invention may produce ananticonvulsant effect through the increase of newly created GABA at thesynaptic junction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

[0239] The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

[0240] The compounds of the instant invention are also expected to beuseful in the treatment of anxiety and of panic as demonstrated by meansof standard pharmacological procedures.

[0241] The compounds of the invention are also expected to be useful inthe treatment of sleep disorders. Sleep disorders are disturbances thataffect the ability to fall and/or stay asleep, that involves sleeping tomuch, or that result in abnormal behavior associated with sleep. Thedisorders include, for example, insomnia, drug-associated sleeplessness,hypersomnia, narcolepsy, sleep apnea syndromes, and parasomnias.

[0242] The compounds of the invention are also useful in the treatmentof arthritis. TABLE 2 Biological Activity [³H] GBP AnxiolyticAnticonvulsant Binding Activity* % Protect* Example (IC₅₀, μM) % Preg.Act. 1 h 2 h Pregabalin 0.218 100 100 (3S,4R)3-Aminomethyl- 2.2 12 20 204,5-dimethyl-hexanoic acid (3R,4S)3-Aminomethyl- 1.7 58 20 04,5-dimethyl-hexanoic acid (3R,4R)3-Aminomethyl- 0.022 204 100 1004,5-dimethyl-hexanoic acid 3-Aminomethyl-5- 0.092 79 60 100methylheptanoic acid 3-Aminomethyl-5- 0.019 NT 40 100 methyloctanoicacid 3-Aminomethyl-5- 0.150 NT 0 0 methyldecanoic acid 3-Aminomethyl-5-0.178 NT 40 80 methylnonanoic acid 3-Aminomethyl-5- 0.163 NT NTmethylundecanoic acid (3S,5R)-3-Aminomethyl- On test On test 80 1005-methyl-heptanoic acid (3S,5R)-3-Aminomethyl- 0.012 160 100 1005-methyl-octanoic acid hydrochloride (3S,5R)-3-Aminomethyl- 0.026 125.94100 100 5-methyl-nonanoic acid hydrochloride (3S,5R)-3-Aminomethyl-0.0297 105.59 100 100 5-methyl-decanoic acid (3S,5S)-3-Aminomethyl- Ontest On test 0 0 5-methyl-heptanoic acid (3S,5S)-3-Aminomethyl- 1.2 15.60 20 5-methyl-octanoic acid (3S,5S)-3-Aminomethyl- On test On test 0 05-methyl-nonanoic acid 3-Aminomethyl-5- 9.08 NT 0 0 methyl-6-phenyl-hexanoic acid 3-Aminomethyl-5,7,7- >10 NT NT trimethyl-octanoic acid(S)-3-Aminomethyl-5- 0.0126 135.38 100 100 methyl-octanoic acid3-Aminomethyl-5,7- 0.359 NT NT dimethyl-octanoic acid3-Aminomethyl-6,6,6- 4.69 NT 0 0 trifluoro-5-methyl- hexanoic acid3-Aminomethyl-5- >10 NT 0 0 methyl-oct-7-enoic acid (S)-3-Aminomethyl-6-On test On test 0 0 methoxy-5-methyl- hexanoic acid 3-aminomethyl-4-0.671 NT NT isopropyl-heptanoic acid 3-aminomethyl-4- 5.4 NT 0 0isopropyl-octanoic acid 3-aminomethyl-4- 0.49 NT 0 0 isopropyl-hexanoicacid 3-Aminomethyl-5- NT 0 0 methyl-4-phenyl- hexanoic acid(S)-3-Aminomethyl-6- 0.605 NT NT fluoro-5-methyl- hexanoic acid3-Aminomethyl-5- 7.3 NT NT cyclohexyl-hexanoic acid 3-Aminomethyl-5- >10cyclopentyl-hexanoic acid 3-Aminomethyl-5- 10.1 NT NT phenyl-hexanoicacid (3S,5S)-3-Aminomethyl- On test On test 0 20 5-methyl-decanoic acid

[0243] The compounds of the instant invention are useful as anxiolyticsand anticonvulsants as shown in Table 2 above. They are compared topregabalin which is isobutylgaba or (S)-3-(Aminomethyl)-5-methylhexanoicacid of formula

Material and Methods

[0244] Carrageenin-Induced Hyperalgesia

[0245] Nociceptive pressure thresholds were measured in the rat pawpressure test using an analgesimeter (Randall-Selitto method: Randall L.O. and Selitto J. J., “A method for measurement of analgesic activity oninflamed tissue,” Arch. Int. Pharmacodyn., 1957;4:409-419). MaleSprague-Dawley rats (70-90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3-300 mg, s.c.), morphine (3 mg/kg, s.c.) orsaline at 3.5 hours after carrageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours postcarrageenin.

[0246] (R)-2-Aza-spiro[4.5]decane-4-carboxylic acid hydrochloride wastested in the above carrageenan-induced hyperalgesia model. The compoundwas dosed orally at 30 mg/kg, and 1 hour postdose gave a percent ofmaximum possible effect (MPE) of 53%. At 2 hours postdose, it gave only4.6% of MPE.

[0247] Semicarbazide-Induced Tonic Seizures

[0248] Tonic seizures in mice are induced by subcutaneous administrationof semicarbazide (750 mg/kg). The latency to the tonic extension offorepaws is noted. Any mice not convulsing within 2 hours aftersemicarbazide are considered protected and given a maximum latency scoreof 120 minutes.

[0249] Animals

[0250] Male Hooded Lister rats (200-250 g) are obtained from Interfauna(Huntingdon, UK) and male TO mice (20-25 g) are obtained from Bantin andKingman (Hull, UK). Both rodent species are housed in groups of six. TenCommon Marmosets (Callithrix Jacchus) weighing between 280 and 360 g,bred at Manchester University Medical School (Manchester, UK) are housedin pairs. All animals are housed under a 12-hour light/dark cycle(lights on at 07.00 hour) and with food and water ad libitum.

[0251] Drug Administration

[0252] Drugs are administered either intraperitoneally (IP) orsubcutaneously (SC) 40 minutes before the test in a volume of 1 mL/kgfor rats and marmosets and 10 mL/kg for mice.

[0253] Mouse Light/Dark Box

[0254] The apparatus is an open-topped box, 45 cm long, 27 cm wide, and27 cm high, divided into a small (2/5) and a large (3/5) area by apartition that extended 20 cm above the walls (Costall B., et al.,“Exploration of mice in a black and white box: validation as a model ofanxiety,” Pharmacol. Biochem. Behav., 1989;32:777-785).

[0255] There is a 7.5×7.5 cm opening in the center of the partition atfloor level. The small compartment is painted black and the largecompartment white. The white compartment is illuminated by a 60-Wtungsten bulb. The laboratory is illuminated by red light. Each mouse istested by placing it in the center of the white area and allowing it toexplore the novel environment for 5 minutes. The time spent in theilluminated side is measured (Kilfoil T., et al., “Effects of anxiolyticand anxiogenic drugs on exploratory activity in a simple model ofanxiety in mice,” Neuropharmacol., 1989;28:901-905).

[0256] Rat Elevated X-Maze

[0257] A standard elevated X-maze (Handley S. L., et al., “Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior,” Naunyn-Schiedeberg's Arch. Pharmacol.,1984;327: 1-5), was automated as previously described (Field, et al.,“Automation of the rat elevated X-maze test of anxiety,” Br. J.Pharmacol., 1991;102(Suppl.):304P). The animals are placed on the centerof the X-maze facing one of the open arms. For determining anxiolyticeffects the entries and time spent on the end half sections of the openarms is measured during the 5-minute test period (Costall, et al., “Useof the elevated plus maze to assess anxiolytic potential in the rat,”Br. J. Pharmacol., 1989;96(Suppl.):312p).

[0258] Marmoset Human Threat Test

[0259] The total number of body postures exhibited by the animal towardsthe threat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

[0260] Rat Conflict Test

[0261] Rats are trained to press levers for food reward in operantchambers. The schedule consists of alternations of four 4-minuteunpunished periods on variable interval of 30 seconds signaled bychamber lights on and three 3-minute punished periods on fixed ratio 5(by footshock concomitant to food delivery) signaled by chamber lightsoff. The degree of footshock is adjusted for each rat to obtainapproximately 80% to 90% suppression of responding in comparison withunpunished responding. Rats receive saline vehicle on training days.

[0262] DBA2 Mouse Model of Anticonvulsant Efficacy

[0263] All procedures were carried out in compliance with the NIH Guidefor the Care and Use of Laboratory Animals under a protocol approved bythe Parke-Davis Animal Use Committee. Male DBA/2 mice, 3 to 4 weeks oldwere obtained from Jackson Laboratories, Bar Harbour, Me. Immediatelybefore anticonvulsant testing, mice were placed upon a wire mesh, 4inches square, suspended from a steel rod. The square was slowlyinverted through 180° and mice observed for 30 seconds. Any mousefalling from the wire mesh was scored as ataxic (Coughenour L. L.,McLean J. R., Parker R. B., “A new device for the rapid measurement ofimpaired motor function in mice,” Pharm. Biochem. Behav.,1977;6(3):351-3). Mice were placed into an enclosed acrylic plasticchamber (21 cm height, approximately 30 cm diameter) with ahigh-frequency speaker (4 cm diameter) in the center of the top lid. Anaudio signal generator (Protek model B-810) was used to produce acontinuous sinusoidal tone that was swept linearly in frequency between8 kHz and 16 kHz once each 10 msec. The average sound pressure level(SPL) during stimulation was approximately 100 dB at the floor of thechamber. Mice were placed within the chamber and allowed to acclimatizefor one minute. DBA/2 mice in the vehicle-treated group responded to thesound stimulus (applied until tonic extension occurred, or for a maximumof 60 sec) with a characteristic seizure sequence consisting of wildrunning followed by clonic seizures, and later by tonic extension, andfinally by respiratory arrest and death in 80% or more of the mice. Invehicle-treated mice, the entire sequence of seizures to respiratoryarrest lasts approximately 15 to 20 seconds. The incidence of all theseizure phases in the drug-treated and vehicle-treated mice wasrecorded, and the occurrence of tonic seizures were used for calculatinganticonvulsant ED₅₀ values by probit analysis (Litchfield J. T.,Wilcoxon F. “A simplified method for evaluating dose-effectexperiments,” J. Pharmacol., 1949;96:99-113). Mice were used only oncefor testing at each dose point. Groups of DBA/2 mice (n=5-10 per dose)were tested for sound-induced seizure responses 2 hours (previouslydetermined time of peak effect) after given drug orally. All drugs inthe present study were dissolved in distilled water and given by oralgavage in a volume of 10 mL/kg of body weight. Compounds that areinsoluble will be suspended in 1% carboxymethocellulose. Doses areexpressed as weight of the active drug moiety.

[0264] The compounds of the instant invention are also expected to beuseful in the treatment of pain and phobic disorders (Am. J. PainManag., 1995;5:7-9).

[0265] The compounds of the instant invention are also expected to beuseful in treating the symptoms of manic, acute or chronic, singleupside, or recurring depression. They are also expected to be useful intreating and/or preventing bipolar disorder (U.S. Pat. No. 5,510,381).

[0266] The compounds of the invention are also expected to be useful insleep disorders. The assessment is as described in Drug Dev Res1988;14:151-159.

[0267] The compounds of the present invention can be prepared andadministered in a wide variety of oral and parenteral dosage forms.Thus, the compounds of the present invention can be administered byinjection, that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

[0268] For preparing pharmaceutical compositions from the compounds ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

[0269] In powders, the carrier is a finely divided solid which is in amixture with the finely divided active component.

[0270] In tablets, the active component is mixed with the carrier havingthe necessary binding properties in suitable proportions and compactedin the shape and size desired.

[0271] The powders and tablets preferably contain from five or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0272] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

[0273] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection liquid preparations can be formulated in solutionin aqueous polyethylene glycol solution.

[0274] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, stabilizing and thickening agents as desired.

[0275] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0276] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0277] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0278] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

[0279] In therapeutic use, the compounds utilized in the pharmaceuticalmethod of this invention are administered at the initial dosage of about0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

[0280] The following examples are illustrative of the instant invention;they are not intended to limit the scope.

[0281] General Synthetic Schemes

[0282] Generic Description

[0283] Method 1

[0284] Method 2

SPECIFIC EXAMPLES Synthesis of Example 1 3-Aminomethyl-5-methylheptanoicAcid

[0285]

[0286] 3-Methyl-1-pentanal 11

[0287] To a stirred suspension of pyridinum dichromate (112.17 g, 298.1mmol) in dichloromethane 500 mL was added 3-methyl-1-pentanol 10 (15 g,146.79 mmol). After stirring for 2.5 hours, ether 400 mL was added, andstirring was continued for another 5 minutes. The filtrate from themixture was concentrated to a small volume and applied to a column ofFlorisil. The compound was eluted with petroleum ether, and furtherchromatographed on silica gel column using 10% ether in petroleum etheras eluent gave 11 (6.5 g, 44%).

[0288]¹H-NMR (CDCl₃) δ 9.72, (d, —CHO), 2.38 (dd, 1H, —CH ₂CHO), 2.19(dd, 1H, —CH ₂CHO), 1.95 (m, 1H, C₂H₅(CH₃)CHCH₂—), 1.4-1.0 (m), 0.9-0.8(m).

[0289] Ethyl 5-methyl-2-heptenoate 12

[0290] Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed withhexane and suspended in dimethoxyethane 60 mL. While cooling in icewater bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes.The reaction was stirred for 15 minutes at 0° C. and a solution of3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in imethoxyethane 20 mL wasadded. After refluxing overnight, it was concentrated, water and hexanewere added, the organic phase was separated, and the aqueous portiondiscarded. The solution was washed twice with brine and dried onmagnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%).

[0291]¹H-NMR (CDCl₃) δ 6.89 (m, 1H, —CH₂CH:CHCOOEt), 5.77 (d, 1H,—CH₂CH:CHCOOEt), 4.16 (q, 2H, —COOCH ₂CH₃), 2.15 and 1.98 (1H each and amultiplet, —CH ₂CH:CHCOOEt), 1.48 (m, 1H, C₂H₅(CH₃)CHCH₂), 1.30-1.10(m), and 0.83.

[0292] Ethyl 5-methyl-3-nitromethylheptanoate 13

[0293] Ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g,39.7 mmol), nitromethane (21.97 g, 359.9 mmol) in acetonitrile 80 mL wasstirred at room temperature under nitrogen atmosphere overnight. Themixture was concentrated to an oil. A solution of the oil in ether waswashed with 1N HCl, brine and dried. It was evaporated to give a lightoil which was chromatographed on silica gel, eluting with 5% to 10%ether in Pet. ether to give 13 (3.6 g, 42%).

[0294]¹H-NMR (CDCl₃) δ 4.49-4.39 (m), 4.12-4.07 (m), 3.61 (m), 2.36 (m),1.36-1.18 (m), 0.86-0.79.

[0295] 3-Aminomethyl-5-methylheptanoic acid (Example 1)

[0296] Ethyl 5-methyl-3-nitromethylheptanoate 13 (3.6 g) washydrogenated in ethanol in the presence of 20% Pd/C and evaporated togive 14. Six normal hydrochloric acid 30 mL was added and refluxedovernight. The solvent was evaporated at reduced pressure, and theresidue was azeotroped with toluene. Aqueous solution of the residue wasapplied to Dowex 50WX 8-100 ion exchange resin that had been washed toneutral pH with HPLC grade water. The column was eluted with water untileluent was neutral pH, and then with 0.5N. NH₄OH solution to givefactions containing 3-aminomethyl-5-methylheptanoic acid. The fractionswere combined and further chromatographed on a C₁₈ column. The compoundwas eluted with 40% water in methanol and crystallized frommethanol-ether to give Example 1 630 mg. ¹H-NMR (CD₃OD) δ 2.83 (m, 1H),2.75 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 1.95 (1H, bs), 1.38 (1H, m),1.3-1.15 (m, 2H), 1.14-0.95 (m, 2H). 0.80 (m, 2CH₃). MS found molecularion at (M+1) 174 and other ions at 156, 139, and 102. Anal. Calcd. forC₉H₁₉NO₂: C, 62.39; H 11.05; N 8.08. Found C, 62.00; H, 10.83; N, 7.98.

[0297] In a similar way the following examples can be prepared.

[0298] 3-Aminomethyl-5-methyl-heptanoic acid;

[0299] 3-Aminomethyl-5-methyl-octanoic acid;

[0300] 3-Aminomethyl-5-methyl-nonanoic acid;

[0301] 3-Aminomethyl-5-methyl-decanoic acid;

[0302] 3-Aminomethyl-5-methyl-undecanoic acid;

[0303] 3-Aminomethyl-5-methyl-dodecanoic acid;

[0304] 3-Aminomethyl-5-methyl-tridecanoic acid;

[0305] 3-Aminomethyl-5-cyclopropyl-hexanoic acid;

[0306] 3-Aminomethyl-5-cyclobutyl-hexanoic acid;

[0307] 3-Aminomethyl-5-cyclopentyl-hexanoic acid;

[0308] 3-Aminomethyl-5-cyclohexyl-hexanoic acid;

[0309] 3-Aminomethyl-5-trifluoromethyl-hexanoic acid;

[0310] 3-Aminomethyl-5-phenyl-hexanoic acid;

[0311] 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid;

[0312] 3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid;

[0313] 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid;

[0314] 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid;

[0315] 3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid;

[0316] 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and

[0317] 3-Aminomethyl-5-(phenylmethyl)-hexanoic acid.

Synthesis of Example 2 (3R,4S)3-Aminomethyl-4,5-dimethyl-hexanoic Acid

[0318]

[0319] Reagents and Conditions:

[0320] a) (R)-(−)-4-phenyl-2-oxazolidinone, (CH₃)₃CCOCl, Et₃N, LiCl,THF, -20 to 23° C.;

[0321] b) MeMgCl, CuBrSMe₂, THF, −35° C.;

[0322] c) NaHMDS, BrCH₂Co2tBu, THF, −78° C. to −40° C.;

[0323] d) LiOH, H₂O₂, THf, H₂O, 25° C.;

[0324] e) BH₃SMe₂, THF, 0 to 25° C.;

[0325] f) pTsCl, pyridine, 25° C.;

[0326] g) NaN₃, DMSO, 60° C.;

[0327] h) Raney nickel, MeOH, H₂; i) 3M HCl, reflux, ion exchange resin(Dowex 50WX8, strongly acidic).

[0328] [R-(E)]3-(4-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one 16

[0329] Trimethylacetyl chloride (7.8 g, 0.065 mol) was added to acid 14(6.9 g, 0.06 mol) and triethylamine (18 g, 0.187 mol) in THF (200 mL) at−20° C. After 1 hour, lithium chloride (2.35 g, 0.55 mol) and(R)-(−)-4-phenyl-2-oxazolidinone (8.15 g, 0.05 mol) were added and thethick suspension warmed to room temperature. After 20 hours, thesuspension was filtered and the filtrate concentrated. The resultantsolid was recrystallized from hexane/ethyl acetate (5:1) to give theoxazolidinone 16 as a white solid (8.83 g, 68%). ¹H NMR (CDCl₃) δ 7.35(m, 5H), 7.18 (dd, 1H, J=15.4 and 1.2 Hz), 7.02 (dd, 1H, J=15.4 and 6.8Hz), 5.45 (dd, 1H, J=8.8 and 3.9 Hz), 4.68 (t, 1H, J=8.8 Hz), 4.22 (dd,1H, J=8.8 and 3.9 Hz), 2.50 (m, 1H), 1.04 (d, 1H, J=1.4 Hz), 1.02 (d,1H, J=1.4 Hz). MS, m/z (relative intensity): 260 [M+H, 100%].

[0330] (3R,3R*)3-(3,4-Dimethyl-pentanoyl)-4-phenyl-oxazolidin-2-one 17

[0331] To copper(I) bromide-dimethyl sulphide complex in THf (45 mL) at−20° C. was added methylmagnesium chloride (as a 3 M solution in THF).After 20 minutes, the oxazolidinone 16 (3.69 g, 0.014 mol) in THf (20mL) was added dropwise over 10 minutes. After 2.5 hours, the reactionwas quenched through the addition of a saturated aqueous solution ofammonium chloride. The resultant two layers were separated and theaqueous phase extracted with ether. The combined organic phases werewashed with 1 M hydrochloric acid, then with 5% aqueous ammoniumhydroxide. The organic phases were dried (MgSO₄) and concentrated togive the oxazolidinone 17 as a white solid (3.39 g, 88%). ¹H NMR (CDCl₃)δ 7.30 (m, 1H), 5.40 (dd, 1H, J=8.8 and 3.7 Hz), 4.63 (t, 1H, J=8.8 Hz),4.21 (dd, 1H, J=8.8 and 3.7 Hz), 2.85 (dd, 1H, J=16.1 and 5.6 Hz), 2.8(dd, 1H, J=16.1 and 8.5 Hz), 1.90 (m, 1H), 1.56 (m, 2H), 0.83 (d, 3H,J=6.8 Hz), 0.78 (d, 3H, J=6.8 Hz), 0.75 (d, 3H, J=6.8 Hz). MS, m/z(relative intensity): 276 [M+H, 100%].

[0332][3R-(3R*(R*),4S*)-]4,5-Dimethyl-3-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-hexanoicAcid Tert-Butyl Ester 18

[0333] Sodium bis(trimethylsilyl)amide (14.4 mL, 0.014 mol of a 1 Msolution in THF) was added to a solution of the oxazolidinone 17 (3.37g, 0.012 mol) in THF (35 mL) at −78° C. After 35 minutes, tert-butylbromoacetate (3.5 g, 0.018 mol) was added and the solution immediatelywarmed to −40° C. After 3 hours, the reaction was quenched through theaddition of a saturated aqueous solution of ammonium chloride. Theresultant two layers were separated and the aqueous phase extracted withether. The combined organic phases were dried (MgSO₄) and concentrated.Flash chromatography (9:1 to 5:1 hexane/ethyl acetate gradient) gave theester 18 (3.81 g, 82%) as a white solid. ¹H NMR (CDCl₃) δ 7.35 (m, 5H),5.37 (dd, 1H, J=8.4 and 3.1 Hz), 4.67 (t, 1H, J=8.7 Hz), 4.41 (dt, 1H,J=12.0 and 3.5 Hz), 4.25 (dd, 1H, J=8.68 and 3.1 Hz), 2.65 (dd, 1H,J=16.9 and 12.0 Hz), 2.25 (dd, 1H, J=16.9 and 3.5 Hz), 1.6 (m, 1H), 1.45(m, 1H), 1.23 (s, 9H), 1.02 (d, 1H, J=6.5 Hz), 0.93 (d, 1H, J=6.7 Hz),0.80 (d, 1H, J=7.0 Hz). MS, m/z (relative intensity): 429 [M−H+CH₃CN,100%], 388 [M−H, 20%].

[0334] (3R,4S)-2-(1,2-Dimethyl-propyl)-succinic Acid 4-tert-butyl Ester19

[0335] To the oxazolidinone 18 (3.62 g, 9.3 mmol) in THF (54 mL)/water(15 mL) was added a premixed solution of lithium hydroxide (20 mL of a0.8 M aqueous solution, 0.016 mol)/H₂O₂ (5.76 mL of a 30% aqueoussolution). After 7 hours, the solution was diluted with water and sodiumbisulfite added (˜10 g). After stirring for a further 0.5 hours, the twolayers were separated and the aqueous phase extracted with ether. Theaqueous phase was then rendered acidic (pH 2) with 1 M hydrochloric acidand extracted with ether. The combined organic phases were dried (MgSO₄)and concentrated. Flash chromatography (5:1 hexane/ethyl acetate) gavethe acid 19 (2.1 g, 95%) as a colorless oil.

[0336]¹H NMR (CDCl₃) δ 3.0 (m, 1H), 2.55 (dd, 1H, J=16.6 and 11.2 Hz),2.27 (dd, 1H, J=16.6 and 3.4 Hz), 1.70 (m, 1H), 1.53 (m, 1H), 1.45 (m,1H), 1.43 (s, 9H), 0.95 (d, 1H, J=6.8 Hz), 0.90 (d, 1H, J=6.6 Hz), 0.83(d, 1H, J=6.8 Hz). MS, m/z (relative intensity): 243 [M−H, 100%].

[0337] (3R,4S)-3-Hydroxymethyl-4,5-dimethyl-hexanoic Acid tert-butylEster 20

[0338] Borane-methyl sulfide complex (16 mL, 0.032 mol of a 2 M solutionin THF) was added to a stirred solution of the acid 19 (1.96 g, 8 mmol)in THF (20 mL) at 0° C. After 20 hours, methanol was added untileffervescence ceased and the solution concentrated. Flash chromatography(5:1 hexane/ethyl acetate gradient) gave the alcohol 20 (1.29 g, 70%) asa colorless oil. ¹H NMR (CDCl₃) δ 3.62 (m, 1H), 2.32 (m, 1H), 2.14 (m,1H), 1.6 (m, 1H), 1.45 (s, 9H), 1.35 (m, 1H), 0.93 (d, 1H, J=6.8 Hz),0.86 (d, 1H, J=6.8 Hz), 0.77 (d, 1H, J=6.9 Hz). MS, m/z (relativeintensity): 175 [M-tBu, 100%].

[0339] (3R,4S)-4,5-Dimethyl-3-(toluene-4-sulfonyloxymethyl)-hexanoicAcid tert-butyl Ester 21

[0340] p-Toluenesulfonyl chloride (847 mg, 4.4 mmol) was added to astirred solution of the alcohol 6 (850 mg, 3.7 mmol), DMAP (10 mg, 0.08mmol) and triethylamine (1.23 mL, 8.88 mmol) in CH₂Cl₂ (20 mL) at 0° C.and the solution warmed to room temperature. After 15 hours, thesolution was washed with 1N hydrochloric acid then with brine. Thecombined organic phases were dried (MgSO₄) and concentrated. Flashchromatography (100 to 92% hexane/ethyl acetate gradient) gave thetosylate 7 (1.22 g, 86%) as a thick gum. ¹H NMR (CDCl₃) δ 7.80 (d, 2H,J=8.2 Hz), 7.25 (d, 2H, J=8.2 Hz), 3.92 (m, 1H), 2.38 (s, 3H), 2.20 (m,2H), 1.95 (m, 1H), 1.40 (m, 1H), 1.32 (s, 9H), 1.27 (m, 1H), 0.78 (d,1H, J=6.6 Hz), 0.73 (d, 1H, J=6.6 Hz), 0.63 (d, 1H, J=7.1 Hz). MS, m/z(relative intensity): 311 [85%], 198 [100%], 157 [95%].

[0341] (3R,4S)-3-Azidomethyl-4,5-dimethyl-hexanoic Acid tert-butyl Ester22

[0342] A solution of the tosylate 21 (1.19 g, 3.1 mmol) and sodium azide(402 mg, 6.2 mmol) in DMSO (15 mL) was warmed to 60° C. for 2.5 hours.Water (100 mL) was added and the solution extracted with ether. Thecombined organic phases were dried (MgSO₄) and concentrated. Flashchromatography (9:1 hexane/ethyl acetate) gave the azide 22 (628 mg,80%) as a colorless oil. ¹H NMR (CDCl₃) δ 3.4 (dd, 1H, J=12.21 and 6.11Hz), 3.3 (dd, 1H, J=21.11 and 6.59 Hz), 2.30 (dd, 1H, J=15.14 and 3.66Hz), 2.25 (m, 1H), 2.05 (dd, 1H, J=15.14 and 9.04 Hz), 1.55 (m, 1H),1.45 (s, 9H), 1.35 (m, 1H), 0.95 (d, 1H, J=6.59 Hz), 0.90 (d, 1H, J=6.83Hz), 0.80 (d, 1H, J=7.08 Hz). MS (m/z): (relative intensity): 228 [M−N₂,35%], 172 [M−N₂-tBu, 100%].

[0343] (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic Acid tert-butyl Ester23 and [4R-[4R*(S*)]]-4-(1,2-Dimethyl-propyl)-pyrrolidin-2-one 24

[0344] The azide 8 (640 mg, 2.5 mmol) and Raney nickel (1 g) in methanol(50 mL) were shaken under an atmosphere of hydrogen for 4 hours. Thesolution was filtered and the filtrate concentrated to give a mixture ofthe amine 23 and lactam 24 which was used without further purificationin the next step.

[0345] (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic Acid (Example 2)

[0346] A solution of the amine 23 and lactam 24 (500 mg) in 3 Mhydrochloric acid were heated to reflux for 9 hours, then stirred atroom temperature for 15 hours. The solution was concentrated and theresultant solid subjected to a sequential purification which involvedion exchange chromatography (Dowex 50WX8, strongly acidic), oxalate saltformation then further purification by ion exchange chromatography(Dowex 50WX8, strongly acidic) to give the Example 2 (343 mg) as a whitesolid. ¹H NMR (D₂O) δ 2.87 (m, 2H), 2.22 (dd, 1H, J=15.4 and 3.4 Hz),2.12 (m, 1H), 1.93 (dd, 1H, J=15.4 and 9.5 Hz), 1.38 (m, 1H), 1.12 (m,1H), 0.77 (d, 1H, J=6.6 Hz), 0.74 (d, 1H, J=6.6 Hz), 0.70 (d, 1H, J=6.8Hz). MS, m/z (relative intensity): 174 [M+H, 100%].

[0347] In a similar way, the following examples can be prepared:

[0348] 3-Aminomethyl-4,5-dimethyl-hexanoic acid;

[0349] (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;

[0350] (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid;

[0351] (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;

[0352] 3-Aminomethyl-4-isopropyl-hexanoic acid;

[0353] 3-Aminomethyl-4-isopropyl-heptanoic acid;

[0354] 3-Aminomethyl-4-isopropyl-octanoic acid;

[0355] 3-Aminomethyl-4-isopropyl-nonanoic acid;

[0356] 3-Aminomethyl-4-isopropyl-decanoic acid; and

[0357] 3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid.

[0358] Method 3

[0359] A compound of structure 30 could be prepared from a compound ofstructure 29 by treatment with an aqueous acid such as hydrochloric acidand alike at a temperature between room temperature and reflux. As analternative, a compound of structure 30 can be prepared from a compoundof structure 32 by treatment with trifluoroacetic acid in a solvent suchas CH₂Cl₂ or EtOAc and alike. Compound 32 could be prepared by basemediate hydrolysis of a Boc protected lactam such as compound 31 whichitself could be prepared from a compound of structure 29 by treatmentwith di-tert-butyl dicarbonate in a solvent such as THF and alike. Thetreatment of the Boc-lactam 31 with aqueous sodium hydroxide for examplewould give rise to the acid 32.

[0360] A compound of structure 29 could be prepared from compound ofstructure 28 (n=0) by treatment with sodium or lithium metal in ammonia.Preferably, the reaction is carried out with sodium metal in ammonia.Alternatively, a compound of structure 29 could be prepared fromcompound of structure 28 (n=1 or 2) by treatment with ceric ammoniumnitrate in a mixture of acetonitrile and water. Other methods known inthe literature for the removal of substituted alkoxy benzyl groups fromnitrogen are described in Green, Protective Groups in Organic Synthesis,Wiley, 2 ed, 1991 and could be utilized.

[0361] A compound of structure 28 could be prepared from a compound ofstructure 27 (where LG is a suitable leaving group such as a halide oran alkyl sulphonate, preferably an iodide would be used) bycarbon-carbon bond forming reactions known in the art. Several methodsexist in the literature for the coupling of organohalides or organoalkylsulphonates with organometallic reagents in the presence of variousmetal salts as summarized in Comprehensive Organic Synthesis, volume3:413 which could be utilized. For example, a compound of structure 28could be prepared from a compound of structure 27 (where LG is iodide)by treatment with a suitable secondary halide (chloride or iodide) inthe presence of magnesium metal, iodine and copper bromidedimethylsulphide in a solvent such as tetrahydrofuran and alike.Alternatively the method according to El Marini, Synthesis, 1992:1104could be used. Hence, a compound of structure 28 could be prepared froma compound of structure 27 (where LG is iodide) by treatment withsuitable methyl-substituted secondary halide such as an iodide in thepresence of magnesium, iodine and lithium tetrachlorocuprate in asolvent such as tetrahydrofuran and alike.

[0362] A compound of structure 27 incorporates a suitable leaving group,which would undergo nucleophilic substitution with suitable nucleophile.Examples of such leaving groups include halides such as chloride,bromide, or iodide, and sulphonic esters such as mesylate, tosylate,triflate, nosylate, and alike. A compound of structure 27 (whereLG=iodide) could be prepared from a compound of structure 26 throughtreatment with iodine, triphenylphosphine, and imidazole in a solventsuch as toluene and alike.

[0363] A compound of structure 26 could be prepared from compound ofstructure 25 by treatment with a metal borohydride, such as sodiumborohydride in a solvent such as tetrahydrofuran or DME and alike.

[0364] Compound 25 could be prepared in a similar fashion to theprocedures of Zoretic et al, J. Org. Chem., 1980;45:810-814 or Nielsenet al J. Med. Chem., 1990;33:71-77 using an appropriate benzylamine,such as but not limited to benzylamine, 4-methoxybenzylamine or2,4-dimethoxybenzylamine.

[0365] As an alternative approach, a compound of structure 26 could betreated with sodium metal and ammonia to give4-hydroxymethyl-pyrrolidinone which could be iodinated affording4-iodomethyl-pyrrolidinone. 4-iodomethyl-pyrrolidinone could then becoupled with organometallic reagents according to the above proceduresavoiding protection of the lactam nitrogen as below.

[0366] Analogous to the above methods a lactam of structure 33 (seeNielsen et. al., J. Med. Chem., 1990;33:71-77 for general method ofpreparation) could be employed thus establishing fixed stereochemistryat C3 of the final amino acids.

[0367] Compounds which could be prepared in this manner include:

[0368] 3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;

[0369] 3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid;

[0370] 3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;

[0371] 3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid;

[0372] 3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid;

[0373] 3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;

[0374] 3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid;

[0375] 3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;

[0376] 3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid;

[0377] 3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid;

[0378] 3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid;

[0379] 3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid;

[0380] 3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid;

[0381] 3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid;

[0382] (3S)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

[0383] (3S)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

[0384] (3S)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

[0385] (3S)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

[0386] (3S)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

[0387] (3S)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

[0388] (3S)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

[0389] (3S)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

[0390] (3S)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

[0391] (3S)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

[0392] (3S)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

[0393] (3S)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

[0394] (3S)-3-Aminomethyl-5-methyl-heptanoic acid;

[0395] (3S)-3-Aminomethyl-5-methyl-octanoic acid;

[0396] (3S)-3-Aminomethyl-5-methyl-nonanoic acid;

[0397] (3S)-3-Aminomethyl-5-methyl-decanoic acid;

[0398] (3S)-3-Aminomethyl-5-methyl-undecanoic acid;

[0399] (3S)-3-Aminomethyl-5,7-dimethyl-octanoic acid;

[0400] (3S)-3-Aminomethyl-5,8-dimethyl-nonanoic acid;

[0401] (3S)-3-Aminomethyl-5,9-dimethyl-decanoic acid;

[0402] (3S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid;

[0403] (3S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;

[0404] (3S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid;

[0405] (3S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

[0406] (3S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

[0407] (3S)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

[0408] (3S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;

[0409] (3S)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;

[0410] (3S)-3-Aminomethyl-5-methyl-hept-6-enoic acid;

[0411] (3S)-3-Aminomethyl-5-methyl-oct-7-enoic acid;

[0412] (3S)-3-Aminomethyl-5-methyl-non-8-enoic acid;

[0413] (E)-(3S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0414] (Z)-(3S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0415] (E)-(3S)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0416] (Z)-(3S)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0417] (E)-(3S)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0418] (Z)-(3S)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0419] (E)-(3S)-3-Aminomethyl-5-methyl-dec-7-enoic acid;

[0420] (Z)-(3S)-3-Aminomethyl-5-methyl-dec-7-enoic acid;

[0421] 3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

[0422] 3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

[0423] 3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

[0424] 3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

[0425] 3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

[0426] 3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

[0427] 3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

[0428] 3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

[0429] 3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

[0430] 3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

[0431] 3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

[0432] 3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

[0433] 3-Aminomethyl-5-methyl-heptanoic acid;

[0434] 3-Aminomethyl-5-methyl-octanoic acid;

[0435] 3-Aminomethyl-5-methyl-nonanoic acid;

[0436] 3-Aminomethyl-5-methyl-decanoic acid;

[0437] 3-Aminomethyl-5-methyl-undecanoic acid;

[0438] 3-Aminomethyl-5,7-dimethyl-octanoic acid;

[0439] 3-Aminomethyl-5,8-dimethyl-nonanoic acid;

[0440] 3-Aminomethyl-5,9-dimethyl-decanoic acid;

[0441] 3-Aminomethyl-5,6-dimethyl-heptanoic acid;

[0442] 3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;

[0443] 3-Aminomethyl-5-cyclopropyl-hexanoic acid;

[0444] 3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

[0445] 3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

[0446] 3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

[0447] 3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;

[0448] 3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;

[0449] 3-Aminomethyl-5-methyl-hept-6-enoic acid;

[0450] 3-Aminomethyl-5-methyl-oct-7-enoic acid;

[0451] 3-Aminomethyl-5-methyl-non-8-enoic acid;

[0452] (E)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0453] (Z)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0454] (E)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0455] (Z)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0456] (E)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0457] (Z)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0458] (E)-3-Aminomethyl-5-methyl-dec-7-enoic acid; and

[0459] (Z)-3-Aminomethyl-5-methyl-dec-7-enoic acid.

[0460] Method 4

[0461] A compound of structure 40 could be prepared from compound ofstructure 39 through treatment with diethylaminosulphur trifluoride in asolvent such as methylene chloride at a temperature between −78° C. androom temperature. Other methods for the fluorination of alcohols areknown and could be utilized as exemplified in Wilkinson, Chem. Rev.1992;92:505-519. Compounds of structure 40 can be converted to therequisite γ-amino acid as described in method 3 above.

[0462] A compound of structure 39 could be prepared from compound ofstructure 38 through treatment with osmium tetroxide and sodiumperiodate in a solvent such as THF and water and reduction of theresultant intermediate with sodium borohydride in a solvent such asethanol.

[0463] Compounds of structures 38 and 34 could be prepared from compoundof structure 33 according to the principles described in method 3.

[0464] An alternative procedure for the synthesis of alcohol 39 (n=0)involves the treatment of a compound of structure 36 with a metalborohydride, such as sodium borohydride in a solvent such astetrahydrofuran or DME and alike to give a compound of structure 37, thefluorination of which could be achived in a similar manner to thepreparation of a compound of strucutre 40. A compound of structure 36could be prepared from compound of structure 35 through treatment withsodium or lithium chloride in aqueous DMSO at a temperature between roomtemperature and reflux. Preferably the reaction is carried out usingsodium chloride in aqueous DMSO at reflux. A compound of structure 35could be prepared from compound of structure 34 through treatment with asuitable methyl malonic acid diester, such as dimethyl methylmalonateand alike with sodium hydride in a solvent such as DMSO or THF andalike. Preferably the reaction is carried out by adding NaH to asolution of dimethyl methylmalonate in DMSO followed by the addition ofthe lactam 34 (where LG is preferably iodide or as defined in method 3)pre-dissolved in DMSO.

[0465] Compounds 39 and 37 can be converted to the free amino acidsbearing a hydroxyl group by the methods described above.

[0466] The following compounds could be prepared in this manner:

[0467] (3S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

[0468] (3S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

[0469] (3S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

[0470] (3S)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

[0471] (3S)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;

[0472] (3S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid; and

[0473] (3S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid.

[0474] Method 5

[0475] A compound of structure 41 could be prepared from compound ofstructure 39 through treatment with a suitable alkyl iodide (or alkylsulphonate), such as methyl iodide and alike, and a base such as n-butyllithium or sodium hydride and alike, in a solvent such as DMSO or THFand alike. Preferably the reaction is carried out by adding NaH to asolution of the alcohol in DMSO followed by the addition of the alkyliodide and heating of the reaction mixture at a temperature between roomtemperature and reflux. The conversion of compounds of structure 41 tothe γ-amino acids has been described above.

[0476] Alternatively, compounds of structure 41 could be derived fromcompounds of structure 42 (where LG=iodide, bromide or an sulphonic acidester, as exampled in method 3) by treatment of an appropriate alkoxyanion in a solvent such as DMSO or THF and alike. A compound ofstructure 42 would also serve as a substrate for carbon-carbon bondforming procedures as outlined in method 3.

[0477] Compounds which could be prepared in this manner include:

[0478] (3S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

[0479] (3S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;

[0480] (3S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

[0481] (3S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;

[0482] (3S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

[0483] (3S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid;

[0484] (3S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoicacid;

[0485] (3S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;

[0486] (3S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;

[0487] (3S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

[0488] (3S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;

[0489] (3S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

[0490] (3S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid;and

[0491] (3S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoicacid.

[0492] Method 6

[0493] Compounds of structure 53 could be prepared from a compound ofstructure 45 as shown above and by the general procedures described inHoekstra et. al., Organic Process Research and Development,1997;1:26-38.

[0494] Compounds of structure 45 can be prepared from compounds ofstructure 44 by treatment with a solution of chromium trioxide inwater/sulfuric acid. Alternative methods of cleaving the olefin in 44could be utilized as detailed in Hudlicky, Oxidations in OrganicChemistry, ACS Monograph 186, ACS 1990:77.

[0495] Compounds of structure 44 (where R₂=alkyl, branched alkyl,cycloalkyl, alkyl-cycloalkyl) could be prepared from (S)-citronellylbromide by carbon-carbon bond forming reactions known in the art and asdescribed in method 3. The substitution of the halide in (S)-citronellylbromide with alkoxy anions could also be used to provide compounds ofstructure 44 where R=alkoxy or phenoxy ethers (and appropriatesubstitutions thereof as according to Formula 1). Alternatively(S)-citronellol could be utilized to afford compounds of structure 44 bytreatment of (S)-citronellol with a base such as sodium hydride, andtreatment of the resultant alkoxide with an appropriate alkyl halide toafford ethers. In another method (S)-citronellyl bromide (or anappropriate sulphonic ester such as, but not limited to, methanesulfonicacid (S)-3,7-dimethyl-oct-6-enyl ester) could be reduced with anappropriate metal borohydride or with an aluminum hydride species, suchas LAH, to provide (R)-2,6-dimethyl-oct-2-ene.

[0496] To one skilled in the art it will be appreciated that rationalchoice of either R- or S-citronellol or R- or S-citronellyl bromidewould give rise to the requisite isomer at C5 of the final amino acid.

[0497] Compounds which could be prepared in this manner include:

[0498] (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;

[0499] (3S,5S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

[0500] (3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;

[0501] (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

[0502] (3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

[0503] (3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

[0504] (3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoicacid;

[0505](3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoicacid;

[0506] (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

[0507] (3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

[0508] (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoicacid;

[0509] (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoicacid;

[0510] (3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoicacid;

[0511] (3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoicacid;

[0512] (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoicacid;

[0513] (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoicacid;

[0514] (3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0515] (3S,5S)-3-Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0516] (3S,5S)-3-Aminomethyl-7-(2-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0517](3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoicacid;

[0518](3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoicacid;

[0519](3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoicacid;

[0520] (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoicacid;

[0521] (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoicacid;

[0522] (3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoicacid;

[0523] (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

[0524] (3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

[0525] (3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

[0526] (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

[0527] (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

[0528] (3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

[0529] (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

[0530] (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

[0531] (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;

[0532] (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid;

[0533] (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid;

[0534] (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid;

[0535] (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid;

[0536] (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid;

[0537] (3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid;

[0538] (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

[0539] (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

[0540] (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;

[0541] (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;

[0542] (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoicacid;

[0543] (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoicacid;

[0544] (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoicacid;

[0545] (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoicacid;

[0546] (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoicacid;

[0547] (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoicacid;

[0548] (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoicacid;

[0549] (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoicacid;

[0550] (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoicacid; and

[0551] (3S,5R)-3-Aminomethyl-5,10-dimethyl-undecanoic acid.

[0552] Method 7

[0553] A compound of structure 58 can be prepared from a compound ofstructure 57 by treatment with borontrifluoride diethyletherate andtriethylsilane in a solvent such as CH₂Cl₂. Alternatively the methoddescribed in Meyers, J. Org. Chem., 1993;58:36-42, could be utilizedthus treating a compound of structure 57 with sodium cyanoborohydride ina solvent such as THF/methanol with 3% HCl in methanol.

[0554] A compound of structure 57 can be prepared from a compound ofstructure 56 by treatment with dimethylamine in a solvent such as DMFand alike according to the procedure of Koot, Tetrahedron Lett.,1992;33:7969-7972.

[0555] A compound of structure 56 can be prepared from a compound ofstructure 54 by treatment of a suitable primary halide 55 (iodide,bromide, or chloride) under standard transmetallation conditions withtBuLi and treatment of the resultant organometallic reagent withsuitable copper salt, such as but not limited to, copper bromide orcopper iodide. The resultant organo-cuprate is added to lactam (see Kootet al, J. Org. Chem., 1992;57:1059-1061 for the preparation of thechiral lactam 54) in a solvent such as THF and alike. The procedure ofKoot, Tetrahedron Lett., 1992;33:7969-7972 exemplifies this method.

[0556] To one skilled in the art it will be appreciated that rationalchoice of either R- or S-primary halides 55 would give rise to therequisite isomer at C5 of the final amino acid.

[0557] Compounds which could be prepared in this manner include:

[0558] (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid;

[0559] (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid;

[0560] (3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid;

[0561] (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid;

[0562] (3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid;

[0563] (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid;

[0564] (3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid;

[0565] (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid;

[0566] (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid;

[0567] (3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid;

[0568] (3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid;

[0569] (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid;

[0570] (3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid;

[0571] (3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid;

[0572] (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid;

[0573] (3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid;

[0574] (3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid;

[0575] (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;

[0576] (3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid;

[0577] (3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid;

[0578] (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid;

[0579] (3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;

[0580] (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

[0581] (3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;

[0582] (3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

[0583] (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

[0584] (3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

[0585] (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid;

[0586](3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoicacid;

[0587] (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

[0588] (3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoicacid;

[0589] (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoicacid;

[0590] (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoicacid;

[0591] (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoicacid;

[0592] (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoicacid;

[0593] (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoicacid;

[0594] (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoicacid;

[0595] (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoicacid;

[0596] (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoicacid;

[0597] (3S,5S)-3-Aminomethyl-5-methyl6-(4-trifluoromethyl-phenoxy)-hexanoic acid;

[0598] (3S,5S)-3-Aminomethyl-5-methyl6-(3-trifluoromethyl-phenoxy)-hexanoic acid;

[0599] (3S,5S)-3-Aminomethyl-5-methyl6-(2-trifluoromethyl-phenoxy)-hexanoic acid;

[0600] (3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;

[0601] (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid;

[0602] (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid;

[0603] (3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

[0604] (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

[0605] (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

[0606] (3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

[0607] (3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

[0608] (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;

[0609] (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid;

[0610] (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid;

[0611] (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid;

[0612] (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid;

[0613] (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid;

[0614] (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid;

[0615] (3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid;

[0616] (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid;

[0617] (3S,5R)-3-Aminomethyl-5,10-dimethyl-undecanoic acid;

[0618] (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid;

[0619] (3S,5S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;

[0620] (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid;

[0621] (3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;

[0622] (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;

[0623] (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;

[0624] (3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;

[0625] (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;

[0626] (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;

[0627] (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid;

[0628] (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;

[0629] (3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid;

[0630] (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoicacid;

[0631] (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoicacid;

[0632] (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoicacid;

[0633] (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid;

[0634] (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;

[0635] (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid;

[0636] (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;

[0637] (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoicacid;

[0638] (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoicacid;

[0639] (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoicacid;

[0640] (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoicacid;

[0641] (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoicacid;

[0642] (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoicacid;

[0643] (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoicacid;

[0644] (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoicacid;

[0645] (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoicacid;

[0646] (3S,5S)-3-Aminomethyl-5-methyl-hept-6-enoic acid;

[0647] (3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid;

[0648] (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid;

[0649] (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0650] (Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;

[0651] (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0652] (E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;

[0653] (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0654] (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;

[0655] (Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid; and

[0656] (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid.

[0657] Method 8

[0658] A compound of structure 60 can be prepared from a compound ofstructure 59 through treatment with an appropriately substituted phenol(including phenol itself) under conditions described by Mitsunobu,Synthesis, 1981:1.

[0659] A compound of structure 59 could be prepared from compound ofstructure 39 by treatment with sodium or lithium metal and alike inammonia. Preferably, the reaction is carried out with sodium metal inammonia.

[0660] The direct hydrolysis of compound 60 would give rise to thedesired amino acid or the approach via hydrolysis of the Boc protectedlactam could be utilized.

[0661] Compounds which could be prepared in this manner include:

[0662] (3S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

[0663] (3S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid;

[0664] (3S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid;

[0665] (3S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid;

[0666] (3S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid;

[0667] (3S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid;

[0668] (3S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;

[0669] (3S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid;

[0670] (3S)-3-Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid;

[0671] (3S,)-3-Aminomethyl-7-(2-methoxy-phenoxy)-5-methyl-heptanoicacid;

[0672](3S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoicacid;

[0673](3S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoicacid;

[0674](3S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoicacid;

[0675] (3S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid;

[0676] (3S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;

[0677] (3S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid;

[0678] (3S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid;

[0679] (3S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid;

[0680] (3S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;

[0681] (3S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid;

[0682] (3S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid;

[0683] (3S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid;

[0684] (3S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid;

[0685] (3S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;

[0686] (3S)-3-Aminomethyl-5-methyl6-(4-trifluoromethyl-phenoxy)-hexanoic acid;

[0687] (3S)-3-Aminomethyl-5-methyl6-(3-trifluoromethyl-phenoxy)-hexanoic acid;

[0688] (3S)-3-Aminomethyl-5-methyl6-(2-trifluoromethyl-phenoxy)-hexanoic acid;

[0689] (3S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;

[0690] (3S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid;

[0691] (3S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid;

[0692] (3S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; and

[0693] (3S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid.

[0694] Method 9 Synthesis of C-4 Substituted Analogs

[0695] A compound of structure 64 could be prepared from compound ofstructure 63 by treatment of 63 with hydrogen at 50 psi in the presenceof a catalyst such as such as Raney nickel in the presence of a basesuch as triethyl amine in an organic solvent for example methanol. Theresulting product is then treated with an aqueous acid such as 6N HCl ata temperature between room temperature and reflux. The resulting mixturecould be subjected to ion exchange chromatography to isolate the product64.

[0696] A compound of structure 63 can be prepared from a compound ofstructure 62B by treatment with an appropriate base, such as but notlimited too sodium hydride, n-butyl lithium and alike, and an alkylatingreagent such as t-butylbromoacetate or benzylbromoacetate in a solventsuch as DMSO or THF an alike. Preferably, the reaction is carried out bytreating a solution of a compound of structure 62B in THF with sodiumhydride and alkylation of the resultant anion with t-butylbromoaceate.

[0697] A compound of structure 62B can be prepared from a compound ofstructure 62A by treatment with sodium chloride in a solvent such asaqueous DMSO at a temperature between 50° C. and reflux.

[0698] A compound of structure 62A can be prepared from a compound ofstructure 61 by treatment with an appropriate alkylmetalhalide such asan alkyllithium reagent or an organomagnesium halide in a solvent suchas THF or ether in the presence of a copper salt, such as but notlimited to copper iodide, copper bromide dimethylsulphide.Alternatively, the reaction may be carried out by the treatment of thenitrile in a solvent such as ether at, or below, room temperature withan alkylmagenisum chloride.

[0699] A compound such as 61 can be prepared according to knownliterature procedures between the condensation of isobutylaldheyde andmethylcyanoacetate.

[0700] Method 10: C-4 Substitution

[0701] Doubly branched 3-substituted GABA analogs 72 can be prepared intwo steps from the azide 71 through hydrogenation of the azide 71 in thepresence of a noble metal catalyst such as 5% palladium on carbon andhydrolysis of the resulting lactam with a strong acid such as 6 N HCl atreflux. The final product 72 can then be isolated using ion exchangechromatography.

[0702] Compound 71 can be prepared in two steps by treatment of alactone such as 70 with HBr in a solvent such as ethanol at atemperature such as 0° C. and reacting the resulting bromide with sodiumazide in a solvent such as dimethyl sulfoxide at a temperature between10° C. and 80° C.

[0703] Lactone 70 can be prepared in two steps by oxidation of acompound such as 69 with an oxidant such as sodium periodate in thepresence of a catalytic amount of ruthenium trichloride in a solventsuch as acetonitrile at a temperature between 0° C. and 100° C. andtreatment of the resulting compound with potassium carbonate in methanolfollowed at a temperature between 25° C. and 70° C. and then treatmentwith an acid such as p-toluene sulfonic acid in a solvent such as THF atreflux or an aqueous acid such as HCl in water at ambient temperature.

[0704] A compound such as 69 can be prepared by a by reduction of acompound such as 68 with a hydride reducing agent such as lithiumaluminum hydride in a solvent such as ether or THF and reaction of theresulting alcohol with an acylating agent such as acetic anhydride inthe presence of a base such as triethyl amine or pyridine or the like.

[0705] Compounds of structure 68 can be prepared by reaction of acompound such as 67 with hydrogen at approximately 50 psi in thepresence of a noble metal catalyst such as 5% palladium on carbon in asolvent such as ethanol. A compound of the formula 67 can be prepared byreaction of a compound of structure 66 with a solution of ethanolsaturated with hydrogen bromide gas. A compound such as 66 can beprepared from a compound such as 65 by treatment of a compound such asone with a strong base such as lithium diisopropyl amine in a solventsuch as THF at a temperature such as −78° C. and reaction of theresulting anion with a compound such as benzyl bromide or benzyl iodide.Compounds of the structure 66 (R═H or loweralkyl) can be prepared inoptical form from methods known in the literature (Davies, J. Org.Chem., 1999;64(23):8501-8508; Koch J. Org. Chem., 1993;58(10):2725-37;Afonso, Tetrahedron, 1993;49(20):4283-92; Bertus, Tetrahedron, Asymmetry1999;10(7):1369-1380; Yamamoto, J. Am. Chem. Soc., 1992;114(20):7652-60).

SPECIFIC EXAMPLES Example 3 Synthesis of 3-Aminomethyl-5-methyl-octanoicAcid

[0706]

[0707] 1-Benzyl-4-hydroxymethyl-pyrrolidine-2-one 74

[0708] Sodium borohydride (8.0 g, 0.211 mol) was added to a solution ofmethyl-1-benzyl-5-oxo-3-pyrrolidnecarboxylate 73 (See Zoretic et al, J.Org. Chem., 1980;45:810-814 for general method of synthesis) (32.0 g,0.137 mol) in 1,2-dimethoxyethane (600 mL) and refluxed for 19 hours.The reaction was cooled to room temperature and 200 mL of water wasadded. The reaction was quenched with 1 M citric acid and concentratedunder reduced pressure. The residue was extracted with dichloromethane,dried over magnesium sulfate, and evaporated to dryness to give 17.47 g,62% of the alcohol 74 as clear oil.

[0709]¹H NMR (CDCl₃) δ 7.30 (m, 5H), 4.38 (d, 1H, J=14.7), 4.46 (d, 1H,J=14.7), 3.56 (m, 2H), 3.36 (m, 1H), 3.10 (m, 1H), 2.52 (m, 2H), 2.26(m, 1H). MS, m/z (relative intensity): 207 [M+2H, 66%]. IR (KBr) 3345,2946, 2866, 1651, 1445, 1025, 737, and 698 cm⁻¹.

[0710] 1-Benzyl-4-iodomethyl-pyrrolidin-2-one 75

[0711] To alcohol lactam 74 (11.18 g, 0.056 mol) in 210 mL toluene wasadded in turn, triphenylphosphine (20.0 g, 0.076 mol), imidazole (10.8g, 0.159 mol), and iodine (19.0 g, 0.075 mol). After stirring thesuspension for 1.5 hours, the supernatant was poured into another flask.The sticky yellow residue was washed twice with ether and the solutionswere combined. The solvent was evaporated and the residue waschromatographed on silica, eluting with 1:1 acetone/hexane to give 7.92g, 46% of the iodolactam 75 as yellow oil. ¹H NMR (CDCl₃) δ 7.25 (m,5H), 4.38 (d, 1H, J=14.6), 4.46 (d, 1H, J=14.6), 3.38 (dd, 1H, J=7.8 and2.2), 3.20 (dd, 1H, J=5.6 and 4.4), 3.12 (dd, 1H, J=7.3 and 2.4), 2.96(dd, 1H, J=5.8 and 4.4), 2.60 (m, 2H), 2.22 (dd, 1H, J=10.5 and 9.7).MS, m/z (relative intensity): 224 [M−H-Bn, 94%], 317 [M+2H, 64%]. IR3027, 2917, 1688, 1438, 1267, and 701 cm⁻¹.

[0712] 1-Benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76

[0713] To a suspension of magnesium turnings (0.50 g, 0.021 mol) in 15mL of dry THF under nitrogen, was added an iodine crystal and2-bromopentane (2.88 g, 0.019 mol). After an exothermic reaction whichwas periodically cooled in an ice bath, the reaction was stirred at roomtemperature for 2 hours. Eight milliliters of Li₂CuCl₄ (made from 84 mgLiCl and 134 mg CuCl₂ in 10 mL of dry THF) was added at 0° C. followedby dropwise addition of 1-Benzyl-4-iodomethyl-pyrolidine-2-one 75 in 15mL dry THF, and the resulting suspension was let stir at 0° C. for 3hours. Stirring was continued at room temperature for 1 hour beforequenching with a saturated solution of ammonium chloride. Water wasadded to dissolve the precipitate formed, and the solution was thenextracted with ether and dried over magnesium sulfate. The solvent wasevaporated under vacuum and the residue chromatographed on silicaeluting with 1:1 acetonethexane to give 1.13 g, 69% of the1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76. ¹H NMR (CDCl₃) δ 7.30(m, 5H), 4.44 (m, 2H), 3.32 (m, 1H), 2.86 (m, 1H), 2.56 (m, 1H), 2.40(m, 1H), 2.10 (m, 1H), 1.30 (m, 6H), 1.10 (m, 1H), 0.90 (m, 6H). MS, m/z(relative intensity): 261 [M+2H, 100%], 301 [M−H+CH₃CN, 82%], 260 [M+H,72%].

[0714] 4-(2-Methyl-pentyl)-pyrrolidin-2-one 77

[0715] A 250 mL 3-neck flask equipped with a dry ice condenser waschilled to −78° C. Ammonia (80 mL) was condensed into the flask and1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 (1.67 g, 0.006 mol) in15 mL THF was added. Freshly cut sodium beads were added until a deepblue color persisted. The cooling bath was removed and the reactionstirred at reflux (−33° C.) for 1 hour. The reaction was quenched withammonium chloride and the excess ammonia was allowed to evaporate. Theresulting residue was diluted with water, extracted withdichloromethane, and dried over magnesium sulfate. Evaporation of thesolvent followed by chromatography on silica eluting with 1:1acetone/hexane gave 0.94 g, 86% of the4-(2-Methyl-pentyl)-pyrrolidin-2-one 77. ¹H NMR (CDCl₃) δ 6.25 (br, 1H),3.44 (m, 1H), 2.95 (m, 1H), 2.54 (m, 1H), 2.40 (m, 1H), 1.98 (m, 1H),1.30 (m, 6H), 0.80 (m, 6H). MS, m/z (relative intensity): 212[M+2H+CH₃CN, 100%], 171 [M+2H, 72%], 170 [M+1H, 65%].

[0716] 3-Aminomethyl-5-methyl-octanoic acid (Example 3)

[0717] The 4-(2-methyl-pentyl)-pyrrolidin-2-one 77 (0.94 g, 0.007 mol)was dissolved in 70 mL of 6N HCl and refluxed for 20 hours. The solutionwas evaporated under vacuum and an aqueous solution of the residue wasapplied to Dowex 50WX 8-100 (strongly acidic) ion exchange resin thathad been washed with HPLC grade water. The column was eluted, first withwater until the eluent was at constant pH, and then with 5% ammoniumhydroxide solution. The ammonium hydroxide fractions were evaporated andazeotroped with toluene. The white solid was washed with acetonefiltered and dried in a vacuum oven for 24 hours to give the amino acid0.61 g, 59%. ¹H NMR (CD₃OD) δ 3.00 (m, 1H), 2.85 (m, 1H), 2.48 (m, 1H),2.30 (m, 1H), 2.14 (brm, 1H), 1.60 (brm, 1H), 1.38 (m, 4H), 1.18 (m,2H), 0.60 (m, 6H). MS, m/z (relative intensity): 188 [M+H, 100%].

Example 4 Synthesis of 3-Aminomethyl-5,7-dimethyl-octanoic Acid

[0718]

[0719] 1-(4-Methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic Acid MethylEster 79

[0720] To 4-methoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at0° C. was added the dimethyl itaconate (48 g, 0.306 mol) in methanol (13mL). The solution was stirred at room temperature for 4 days. 1N HCl wasadded to the solution followed by ether. The two layers were separatedand the aqueous phase extracted with ether. The combined organic phaseswere dried (MgSO₄). Upon filtration of the drying agent the desiredmaterial 79 precipitated from solution that was collected and driedunder vacuum. 23.26 g, 29%. MS, m/z (relative intensity): 264 [M+H,100%]. Anal. Calcd for C₁₄H₁₇N₁O₄: C, 63.87; H, 6.51; N, 5.32. Found: C,63.96; H, 6.55; N, 5.29.

[0721] 4-Hydroxymethyl-1-(4-methoxy-benzyl)-pyrrolidine-2-one 80

[0722] NaBH₄ (15 g, 0.081 mol) was added in portions to ester 79 inethanol (600 mL) at room temperature. After 4.5 hours water (˜200 mL)was carefully added to the reaction and the solution stirred at roomtemperature overnight. The resultant solid was removed by filtration andthe filtrate concentrated to give alcohol 80 as an oil. 15.33 g, 81%.MS, m/z (relative intensity): 235 [M+H, 100%].

[0723] 4-Iodomethyl-1-(4-methoxy-benzyl)-pyrrolidin-2-one 81

[0724] To alcohol 80 (12.9 g, 0.055 mol) in PhMe was addedtriphenylphosphine (20 g, 0.077 mol), imidazole (10.8 g, 0.16 mol), andiodine (19 g, 0.075 mol). The suspension was stirred at room temperature5 hours. A saturated aqueous solution of sodium thiosulphate was addedand the two layers separated. The aqueous phase was extracted with etherand the combined organic phases washed with brine, dried (MgSO₄) andconcentrated. Flash chromatography (6:1 to 4:1 toluene/acetone) of theresidue gave iodide 81 as an oil. 11.9 g, 63%. MS, m/z (relativeintensity): 346 [M+H, 100%].

[0725] 4-(2,4-Dimethyl-pentyl)-1-(4-methoxy-benzyl)-pyrrolidin-2-one 82

[0726] A procedure similar to the preparation of1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 was utilized to give4-(2,4-dimethyl-pentyl)-1-(4-methoxy-benzyl)-pyrrolidin-2-one as an oil.1.22 g, 29%. MS, m/z (relative intensity): 304 [M+H, 100%].

[0727] 4-(2,4-Dimethyl-pentyl)-pyrrolidin-2-one 83

[0728] To the lactam (1.17 g, 3.86 mmol) in MeCN (20 mL) at 0° C. wasadded ceric ammonium nitrate (4.2 g, 7.7 mmol) in H₂O (10 mL). After 50minutes a further portion of ceric ammonium nitrate (2.1 g, 3.86 mmol)was added, and after 1 hour the mixture was absorbed onto silica andflash chromatographed to give an oil. MS, m/z (relative intensity): 183[M+H, 100%].

[0729] 3-Aminomethyl-5,7-dimethyl-octanoic Acid (Example 4)

[0730] A procedure similar to the preparation of3-aminomethyl-5-methyl-octanoic acid (Example 3) was utilized to givethe amino acid as a solid. MS, m/z (relative intensity): 202 [M+H,100%].

Example 5 Synthesis of (S)-3-Aminomethyl-5-methyl-octanoic Acid

[0731]

[0732] (S)-4-Hydroxymethyl-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 84

[0733] To the ester 33 (49 g, 0.198 mol) in EtOH (600 mL) was addedsodium borohydride (22 g, 0.595 mol). After 7 hours, 1 M citric acid wascarefully added and, after effervescence had ceased, water was added tofully quench the reaction. The ethanol was removed under reducedpressure and ethyl acetate added. The resultant two layers wereseparated, the aqueous phase was extracted with EtOAc, and the combinedorganic phases dried (MgSO₄) and concentrated to give a heavy oil. MS,m/z (relative intensity): [M+H, 100%].

[0734] (S)-4-Iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 85

[0735] A procedure similar to the iodination of compound 80 was utilizedgiving iodide 85 as an oil. 35.2 g, 56%. Anal. Calcd for C₁₃H₁₆I₁N₁O₁:C, 47.43; H, 4.90; N, 4.25. Found: C, 47.41; H, 4.83; N, 4.17.

[0736] 4-(2-Methyl-pentyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 86

[0737] A procedure similar to the preparation of1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 was utilized to give2.71 g, 81.0% of 86 as an oil. MS, m/z (relative intensity): 274 [M+1H,100%], 315 [M+H+CH₃CN, 65%].

[0738] (S)-4-(2-Methyl-pentyl)-pyrrolidin-2-one 87

[0739] A procedure similar to the preparation of4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was used to give 1.14 g, 72.8%of 87 as an oil. MS, m/z (relative intensity): 170 [M+1H, 10%], 211[M+1H+CH₃CN, 90%].

Example 5 (S)-3-Aminomethyl-5-methyl-octanoic Acid

[0740] A procedure similar to the preparation of3-aminomethyl-5-methyl-octanoic acid (Example 3) was used to give theamino acid (example 5) 0.88 g, 74.3%. ¹H NMR (CD₃OD) δ 2.95 (m, 1H),2.80 (m, 1H), 2.40 (m, 1H), 2.25 (m, 1H), 2.05 (brm, 1H), 1.50 (brm,1H), 1.30 (m, 4H), 1.10 (m, 2H), 0.90 (m, 6H). MS, m/z (relativeintensity): 188 [M+1H, 100%], 186 [M−1H, 100%], 229 [M+1H+CH₃CN, 30%].

Example 6 Synthesis of (S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoicAcid

[0741]

[0742](S)-4-(2-Methyl-pent-4-enyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 88

[0743] A procedure similar to the preparation of1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 was followed giving theadduct 88 as an oil. 6 g, 74%. MS, m/z (relative intensity): 272 [M+H,100%].

[0744](S)-4-(4-Hydroxy-2-methyl-butyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one89

[0745] OsO₄ (2 mL of a 4% wt solution in t-BuOH) was added to the alkene88 (5.8 g, 0.021 mol) in THFIH₂O (3:1, 100 mL). After 1 hour, sodiumperiodate (11.4 g, 0.053 mol) was added. After 2 hours, the suspensionwas filtered and the solids washed with dichloromethane. The filtratewas concentrated and the residue azeotroped with toluene. The residuewas dissolved in ethanol and sodium borohydride (2.5 g) added. Thesuspension was stirred at room temperature overnight. 1N citric acid wasadded and the mixture diluted with ether. The resultant two layers wereseparated and the aqueous phase was extracted with ether and thecombined organic dried (MgSO₄) and concentrated. Flash chromatography(1:1 hexane/EtOAc) of the residue gave an oil. 4.2 g, 73%. MS, m/z(relative intensity): 276 [M+H, 100%].

[0746](S)-4-(4-Methoxy-2-methyl-butyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one90 To alcohol 89 (2 g, 7.66 mmol) in DMSO (60 mL) at room temperaturewas added NaH (368 mg, 60% in oil). After 30 minutes the methyl iodide(1.08 g, 7.66 mmol) was added and the solution stirred at roomtemperature overnight, upon which the reaction was diluted with water(500 mL). The solution was extracted with ether, and the combinedorganic extracts were dried (MgSO₄) and concentrated. Flashchromatography (90% to 50% hexane/acetone) of the residue gave theproduct 90 as an oil (1.1 g, 52%). MS m/z 290 (M+H, 100%).

[0747] (S)-4-(4-Methoxy-2-methyl-butyl)-pyrrolidin-2-one 91

[0748] A procedure similar to the synthesis of4-(2-methyl-pentyl)-pyrrolidin2-one 77 was utilized giving lactam 91 asan oil. MS m/z 186 (M+H, 100%).

Example 6 (S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic Acid

[0749] A procedure similar to the synthesis of example 3 was followed.The resultant amino acid isolated from ion-exchange chromatography wasrecrystallized from methanol/ethyl acetate to give the example 6 as awhite solid. MS m/z 204 (M+H, 100%). Anal. Calcd for C₁₀H₂₁N₁O₃: C,59.09; H, 10.41; N, 6.89. Found: C, 58.71; H, 10.21; N, 6.67.

Example 7 Synthesis of (S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic Acid

[0750]

[0751]2-Methyl-2-[(S)-5-oxo-1-((S)-1-phenyl-ethyl)-pyrrolidin-3-ylmethyl]-malonicAcid Dimethyl Ester 92

[0752] To dimethyl methylmalonate (1.06 g, 7.29 mmol) in DMSO (7 mL) atroom temperature was added NaH (291 mg of a 60% dispersion in oil).After the effervescence had ceased the lactam 85 (2 g, 7.29 mol) in DMSO(5 mL) was added. After 1 hour water was added and the aqueous solutionextracted with ether. The combined organic extracts were dried (MgSO₄)and concentrated. Flash chromatography (1:1 hexane/acetone) of theresidue gave the product as an oil (1.7 g, 81%). MS m/z 348 (M+H, 100%).2-Methyl-3-[(S)-5-oxo-1-((S)-1-phenyl-ethyl)-pyrrolidin-3-yl]-propionicAcid Methyl Ester 93

[0753] The ester 92 (483 mg, 1.4 mmol), NaCl (104 mg, 1.8 mmol), water(105 μL) and DMSO (5 mL) were heated to reflux for 2 hours. The solutionwas cooled to room temperature water was added and the aqueous solutionextracted with ether. The combined organic extracts were dried (MgSO₄)and concentrated. Flash chromatography (80% to 66% hexane/acetone) ofthe residue gave the product as an oil (160 mg, 40%). MS m/z 290 (M+H,100%).

[0754](S)-4-(3-Hydroxy-2-methyl-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one37

[0755] To the ester 93 (4.82 g, 0.017 mol) in EtOH (100 mL) was addedNaBH4 (3.7 g, 0.10 mol) and the mixture heated to reflux for 2.5 hours.The solution was cooled to 0° C. and 1 M citric acid carefully addedfollowed by water. The solution was concentrated to half volume addedand extracted with ether. The combined organic extracts were dried(MgSO₄) and concentrated. Flash chromatography (1:1 hexane/acetone) ofthe residue gave the product as an oil (2.6 g, 59%). MS m/z 262 (M+H,100%).

[0756](S)-4-(3-Fluoro-2-methyl-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one94

[0757] To DAST (1 g, 6.2 mmol) in CH₂Cl₂ (20 mL) at −78° C. was addedthe alcohol 37 in CH₂Cl₂ (10 mL). After 1 hour at −78° C. the solutionwas warmed to room temperature. After 7 hours the solution was carefullyquenched with a saturated aqueous solution of sodium bicarbonate and thetwo layers separated. The organic phase was dried (MgSO₄) andconcentrated. Flash chromatography (90% to 66% hexane/acetone) of theresidue gave the product as an oil (600 mg, 37%). MS m/z 264 (M+H,100%).

[0758] (S)-4-(3-Fluoro-2-methyl-propyl)-pyrrolidin-2-one 95

[0759] A procedure similar to the preparation of4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was utilized affording thelactam as an oil (242 mg, 68%). MS nvz 159 (M, 100%).

(S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic Acid

[0760] A procedure similar to the synthesis of example 3 was followed.The resultant amino acid isolated from ion-exchange chromatography wasrecrystallized from methanol/ethyl acetate to give example 7 as a whitesolid. MS m/z 177 (M, 100%). Anal. Calcd for C₈H₁₆F₁N₁O₂:0.02H₂O: C,54.11; H, 9.10; N, 7.89. Found: C, 53.75; H, 9.24; N, 7.72.

Example 8 Synthesis of (S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoicAcid

[0761]

[0762](S)-4-(3-Methoxy-2-methyl-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one96

[0763] A procedure similar to the synthesis of(S)-4-(4-methoxy-2-methyl-butyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one90. was utilized giving ether 96 as an oil (90 mg, 37%). MS m/z 276(M+H, 100%).

[0764] (S)-4-(3-Methoxy-2-methyl-propyl)-pyrrolidin-2-one 97

[0765] A procedure similar to the synthesis of4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was utilized giving 97 as an oil(760 mg, 93%). MS m/z 171 (M+H, 100%).

(S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic Acid

[0766] A procedure similar to the synthesis of example 3 was followed.The resultant amino acid isolated from ion-exchange chromatography wasrecrystallized from methanol/ethyl acetate to give Example 8 as a whitesolid.

[0767] MS m/z 190 (M+H, 100%). Anal. Calcd for C₉H₁₉N₁O₃: C, 57.12; H,10.12; N, 7.40. Found: C, 57.04; H, 10.37; N, 7.30. A second batchprecipitated from the mother liquors (1:5 ratio of C5 isomers by ¹HNMR). MS m/z 190 (M+H, 100%).

Example 9 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-octanoic AcidHydrochloride

[0768]

[0769] (R)-2,6-Dimethyl-non-2-ene 98

[0770] To (S)-citronellyl bromide (50 g, 0.228 mol) in THF (800 mL) at0° C. was added LiCl (4.3 g) followed by CuCl₂ (6.8 g). After 30 minutesmethylmagnesium chloride (152 mL of a 3 M solution in THF, Aldrich) wasadded and the solution warmed to room temperature. After 10 hours thesolution was cooled to 0° C. and a saturated aqueous solution ofammonium chloride carefully added. The resultant two layers wereseparated and the aqueous phase extracted with ether. The combinedorganic phases were dried (MgSO₄) and concentrated to give an oil. 32.6g; 93%. Used without further purification.

[0771]¹³C NMR (100 MHz; CDCl₃) 131.13, 125.28, 39.50, 37.35, 32.35,25.92, 25.77, 20.31, 19.74, 17.81, 14.60.

[0772] (R)-4-Methyl-heptanoic acid 99

[0773] To alkene 98 (20 g, 0.13 mol) in acetone (433 mL) was added asolution of CrO₃ (39 g, 0.39 mol) in H₂SO₄ (33 mL)/H₂O (146 mL) over 50minutes. After 6 hours a further amount of CrO₃ (26 g, 0.26 mol) inH₂SO₄ (22 mL)/H₂O (100 mL) was added. After 12 hours the solution wasdiluted with brine and the solution extracted with ether. The combinedorganic phases were dried (MgSO₄) and concentrated. Flash chromatography(gradient of 6:1 to 2:1 hexane/EtOAc) gave the product 99 as an oil.12.1 g; 65%. MS, m/z (relative intensity): 143 [M−H, 100%].

[0774](4R,5S)-4-Methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one100

[0775] To the acid 99 (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494mol) in THF (500 mL) at 0° C. was added trimethylacetylchloride (20 g,0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followed by theoxazolidinone (30 g, 0.17 mol). The mixture was warmed to roomtemperature and after 16 hours the filtrate was removed by filtrationand the solution concentrated under reduced pressure. Flashchromatography (7:1 hexane/EtOAc) gave the product 100 as an oil. 31.5g; 79%. [α]D=5.5 (c 1 in CHCl₃). MS, m/z (relative intensity): 304 [M+H,100%].

[0776](3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester 101

[0777] To oxazolidinone 100 (12.1 g, 0.04 mol) in THF (200 ml) at −50°C. was added NaHMDS (48 mL of a 1 M solution in THF). After 30t-butylbromoaceate (15.6 g, 0.08 mol) was added. The solution wasstirred for 4 hours at −50° C. and then warmed to room temperature.After 16 hours a saturated aqueous solution of ammonium chloride wasadded and the two layers separated. The aqueous phase was extracted withether and the combined organic phases dried (MgSO₄) and concentrated.Flash chromatography (9:1 hexane/EtOAc) gave the product 101 as a whitesolid 12 g; 72%. [α]_(D)=30.2 (c 1 in CHCl₃). ¹³C NMR (100 MHz; CDCl₃)176.47, 171.24, 152.72, 133.63, 128.87, 125.86, 80.85, 78.88, 55.34,39.98, 38.77, 38.15, 37.58, 30.60, 28.23, 20.38, 20.13, 14.50, 14.28.

[0778] (S)-2-((R)-2-Methyl-pentyl)-succinic acid 4-tert-butyl Ester 102

[0779] To ester 101 (10.8 g, 0.025 mol) in H₂O (73 mL) and THF (244 mL)at 0° C. was added a premixed solution of LiOH (51.2 mL of a 0.8 Msolution) and H₂O₂ (14.6 mL of a 30% solution). After 4 hours a further12.8 mL LiOH (0.8 M solution) and 3.65 mL of H₂O₂ (30% solution) wasadded. After 30 minutes sodium bisulfite (7 g), sodium sulfite (13 g),and water (60 mL) was added followed by hexane (100 mL) and ether (100mL). The two layers were separated and the aqueous layer extracted withether. The combined organic phases were concentrated to an oil that wasdissolved in heptane (300 mL). The resultant solid was filtered off andthe filtrate dried (MgSO₄) and concentrated to afford an oil (6 g, 93%)which was used without further purification. MS, m/z (relativeintensity): 257 [M+H, 100%].

[0780] (3S,5R)-3-Hydroxymethyl-5-methyl-octanoic Acid tert-butyl Ester103

[0781] To acid 102 (3.68 g, 0.014 mol) in THF (100 mL) at 0° C. wasadded BH₃.Me₂ (36 mL of a 2 M solution in THF, Aldrich) upon which thesolution was warmed to room temperature. After 15 hours ice wascarefully added (in order to control the effervescence) to the solutionfollowed by brine. The solution was extracted with ether and thecombined organic phases dried (MgSO₄) and concentrated under reducedpressure. Flash chromatography (4:1 hexane/EtOAc) gave alcohol 103 as anoil (2.0 g, 59%). ¹³C NMR (100 MHz; CDCl₃) 173.56, 80.85, 65.91, 39.74,39.20, 38.90, 35.65, 29.99, 28.31, 20.18, 19.99, 14.56.

[0782] (3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic Acidtert-butyl Ester 104

[0783] To alcohol 103 (1.98 g, 8.1 mmol) in CH₂Cl₂ (40 mL) at roomtemperature was added triethylamine (2.4 g, 0.024 mol), DMAP (20 mg) andtosyl chloride (2.3 g, 0.012 mol). After 14 hours 1N HCl was added andthe two layers separated. The aqueous phase was extracted with ether andthe combined organic phases dried (MgSO₄) and concentrated. Flashchromatography (95% hexane/EtOAc) gave tosylate 104 as an oil (2.94 g,91%). ¹³C NMR (100 MHz; CDCl₃) 171.60, 144.92, 133.07, 130.02, 128.12,80.80, 72.15, 39.73, 38.09, 37.89, 32.67, 29.71, 28.22, 21.83, 20.10,19.54, 14.49.

[0784] (3S,5R)-3-Azidomethyl-5-methyl-octanoic Acid tert-butyl Ester 105

[0785] Tosylate 104 (2.92 g, 7.3 mmol) and sodium azide (1.43 g, 0.02mol) were warmed to ˜50° C. in DMSO (30 mL). After 2 hours the solutionwas cooled to room temperature and diluted with water. The solution wasextracted with ether and the combined organic phases dried (MgSO₄) andconcentrated to give an oil 1.54 g, 79%. Further purification by flashchromatography (95% hexane/EtOAc) gave an oil. [α]_(D)=−8.3 (c 1 inCHCl₃). ¹³C NMR (100 MHz; CDCl₃) 172.01, 80.73, 54.89, 39.73, 39.46,39.00, 33.40, 29.85, 28.30, 20.15, 19.82, 14.52.

[0786] (S)-4-((R)-2-Methyl-pentyl)-pyrrolidin-2-one 107 and(3S,5R)-3-aminomethyl-5-methyl-octanoic Acid tert-butyl Ester 106

[0787] Azide 105 was treated with 5% Pd/C and shaken under an atmosphereof hydrogen for 20 hours where upon a further 200 mg of 5% Pd/C added.After 6 hours the filtrate was concentrated to afford an oil which by ¹HNMR was found to be a mixture of primary amine 106 and lactam 107 (1.75g) which was used without further purification.

Example 9 (3S,5R)-3-Aminomethyl-5-methyl-octanoic Acid Hydrochloride

[0788] The mixture of the amine 106 and the lactam 107 (1.74 g) wastreated with 3N HCl (40 mL) and the solution warmed to 50° C. for 4hours then cooled to room temperature. After 12 hours the solution wasconcentrated and the residue recrystallized from ethyl acetate to givethe amino acid as a white solid 605 mg. MS, m/z (relative intensity):188 [M+H, 100%]. Anal. Calcd for C₁₀H₂₁N₁O₂:H₁Cl₁ C, 53.68; H, 9.91; N,6.26. Found: C, 53.83; H, 10.12; N, 6.07.

Example 10 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-heptanoic Acid

[0789]

[0790] Methanesulfonic Acid (S)-3,7-dimethyl-oct-6-enyl ester 108

[0791] To S-(−)-citronellol (42.8 g, 0.274 mol) and triethylamine (91nL, 0.657 mol) in CH₂Cl₂ (800 mL) at 0° C. was added methanesulphonylchloride (26 mL, 0.329 mol) in CH₂Cl₂ (200 mL). After 2 hours at 0° C.the solution was washed with 1N HCl then brine. The organic phase wasdried (MgSO₄) and concentrated to afford an oil (60.5 g, 94%) which wasused without further purification. ¹H NMR (400 MHz; CDCl₃) 5.05 (1H, m),4.2 (2H, m), 2.95 (3H, s), 1.98 (2H, m), 1.75 (1H, m), 1.6 (3H,s), 1.5(4H, m), 1.35 (2H, m), 1.2 (1H, m), 0.91 (3H, d, J=6.5 Hz).

[0792] (R)-2,6-Dimethyl-oct-2-ene 109

[0793] To alkene 108 (60 g, 0.256 mol) in THF (1 L) at 0° C. was addedlithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours, a further3.8 g of lithium aluminum hydride was added and the solution warmed toroom temperature. After 18 hours, a further 3.8 g of lithium aluminumhydride was added. After a further 21 hours, the reaction was carefullyquenched with 1N citric acid and the solution diluted further withbrine. The resultant two phases were separated and the organic phase wasdried (MgSO₄) and concentrated to afford an oil which was used withoutfurther purification. MS, m/z (relative intensity): 139 [M−H, 100%].

[0794] (R)-4-Methyl-hexanoic Acid 110

[0795] A procedure similar to the synthesis of (R)-4-methyl-heptanoicacid 99 was utilized giving the acid as an oil (9.3 g, 56%). MS, m/z(relative intensity): 129 [M−H, 100%].

[0796] (4R,5S)-4-Methyl-3-((R)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one 111

[0797] A procedure similar to the synthesis of(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one100 was utilized giving oxazolidinone 111 as an oil (35.7 g, 95%). MS,m/z (relative intensity): 290 [M+H, 100%].

[0798](3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-methanoyl]-heptanoicacid tert-butyl ester 112

[0799] A procedure similar to the preparation of(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester 101 was followed giving 112 as an oil (7.48 g;31%).

[0800] (S)-2-((R)-2-Methyl-butyl)-succinic acid 4-tert-butyl ester 113

[0801] To ester 112 (7.26 g, 0.018 mol) in H₂O (53 mL) and THF (176 mL)at 0° C. was added a premixed solution of LiOH (37 mL of a 0.8 Msolution) and H₂O₂ (10.57 mL of a 30% solution) and the solution warmedto room temperature. After 2 hours sodium bisulfite (7 g), sodiumsulfite (13 g), and water (60 mL) was added and the two layers wereseparated and the aqueous layer extracted with ether. The combinedorganic phases were concentrated to an oil that was dissolved in heptane(200 mL). The resultant solid was filtered off and the filtrate dried(MgSO₄) and concentrated to afford an oil (4.4 g) that was used withoutfurther purification.

[0802] (3S,5R)-3-Hydroxymethyl-5-methyl-heptanoic acid tert-butyl Ester114

[0803] A procedure similar to the preparation of(3S,5R)-3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103 wasutilized giving alcohol 114 as an oil (2.68 g, 69%). MS, m/z (relativeintensity): 216 [89%], 174 [M-(CH₃)₃C, 100%].(3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-heptanoic acidtert-butyl ester 115 To 114 alcohol (2.53 g, 0.011 mmol) in CH₂Cl₂ (140mL) at 0° C. was added pyridine (2.6 g, 0.033 mol), DMAP (100 mg), andtosyl chloride (3.15 g, 0.016 mol) and the solution warmed to roomtemperature for 3.5 hours whereupon more DMAP and TsCl (3.15 g) wereadded. After 14 hours 1N HCl was added and the two layers separated. Theorganic phase was washed with brine then or dried (MgSO₄) andconcentrated. Flash chromatography (95% to 86% hexane/EtOAc) gavetosylate 115 as an oil (1.53 g, 36%). ¹³C NMR (100 MHz; CDCl₃) 130.03,128.12, 72.18, 37.89, 37.71, 32.67, 31.49, 29.88, 28.22, 21.83, 19.07,11.37.

[0804] (3S,5R)-3-Azidomethyl-5-methyl-heptanoic Acid tert-butyl Ester116

[0805] A procedure similar to the preparation of(3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 wasutilized giving an oil 0.956 g, 97%. MS, m/z (relative intensity): 228[M−N₂, 80%].

[0806] (S)-4-((R)-2-Methyl-butyl)-pyrrolidin-2-one 118 and(3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid tert-butyl ester 117

[0807] Azide 116 (689 mg) was treated with 20% Pd/C (90 mg) in THF (20mL) and shaken under an atmosphere of hydrogen for 36 hours. Thecatalyst was removed by filtration and the resultant oil used withoutfurther purification.

Example 10 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic Acid

[0808] The mixture of amine 117 and lactam 118 was treated with 6N HCland the solution warmed to 50° C. for 17 hours then cooled to roomtemperature and concentrated. The resultant oil was subjected toion-exchange chromatography (Dowex, strongly acidic resin) using 5%ammonium hydroxide to give a cream solid which was recrystallized frommethanol/ethyl acetate to give (3S, 5R)-3-aminomethyl-5-methyl-heptanoicacid, example 10. MS, m/z (relative intensity): 174 [M+H, 100%]. Anal.Calcd for C₁₉H₁₉N₁O₂. C, 62.39; H, 11.05; N, 8.08. Found: C, 62.23; H,11.33; N, 7.89.

Example 11 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-octanoic Acid

[0809]

[0810] (S)-2,6-Dimethyl-non-2-ene 119

[0811] CuCl₂ (5.36 g, 39.7 mmol) and LiCl (3.36, 80.0 mmol) were stirredtogether in dry THF (40 mL) for 15 minutes. The resulting solution wasadded to methylmagnesium chloride, 3.0 M in THF (168 mL) at 0° C. undernitrogen atmosphere and stirred at that temperature for 15 minutes. Tothe reaction suspension was added slowly (R)-(−)-Citronellyl bromide(55.16 g, 251.8 mmol) in THF (100 mL), and stirred at 0° C. for 2.5hours. It was warmed to room temperature and stirring was continued foran additional 1 hour. The mixture was cooled to 0° C. and quenched withsaturated ammonium chloride solution. The suspension was then extractedinto ether, washed with water, and dried over MgSO₄ The solution wasconcentrated under reduced pressure to afford 36.3 g; 94% of(S)-2,6-Dimethyl-non-2-ene as an oil. MS, m/z (relative intensity): 153[M−1H, 100%], 194 [M−1H+CH₃CN, 45%].

[0812] (S)-4-Methyl-heptanoic Acid 120

[0813] To the (S)-2,6-Dimethyl-non-2-ene 119 (39.0 g, 253.2 mmol) inacetone (IL) at 0° C. was added Jones reagent (2.7 M, 600 mL) dropwiseover 1.5 hours and let stir at room temperature for 18 hours. Thereaction mixture was poured into a saturated solution of Na₂SO₄ andextracted into ether. It was washed with brine and concentrated invacuo. The oily residue was dissolved in methanol (70 mL) and 1 M NaOH(700 mL) and then stirred for 30 minutes. The aqueous solution waswashed with CH₂Cl₂, acidified with 10% HCl and extracted into CH₂Cl₂.The solution was dried over MgSO₄ and concentrated to dryness to give24.22 g; 66% of (S)-4-Methyl-heptanoic acid as an oil. MS, m/z (relativeintensity): 143 [M−1H, 100%].

[0814](4R,5S)-4-Methyl-3-((S)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one121

[0815] A procedure similar to the preparation of(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one100 was utilized giving(4R,5S)-4-methyl-3-((S)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one121 6.2 g; 80.0%, as an oil. MS, m/z (relative intensity): 304 [M+1H,90%], 355 [M+1H+CH₃CN, 60%].

[0816](3S,5S)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester 122

[0817] n-BuLi, 1.6 M in Hexane (18.0 mL, 30.1 mmol) was added dropwiseto a solution of diisopropylamine (4.6 mL, 32.6 mmol) in dry THF (50 mL)under nitrogen at −5° C. keeping the temperature below 0° C. duringaddition. The mixture was let stir at −5° C. for 20 minutes and thencooled to −78° C. 121 (7.6 g, 25.1 mmol) in dry THF (12 mL) was added tothe LDA solution and stirred at −78° C. for 30 minutes. t-Butylbromoacetate (4.8 mL, 32.6 mmol) as added to the reaction and stirring at−78° C. was continued for 2 hours. It was let warm to room temperaturebefore stirring for an additional 18 hours. The reaction was quenchedwith a saturated solution NaH₂PO₄, extracted into ethylacetate, anddried over MgSO₄. The solution was concentrated to give a solid residuewhich was dissolved in hot hexane. The hexane solution was allowed tocool to room temperature before cooling further in an ice bath. Theresulting precipitate was collected and allowed to air dry to give 122as a fluffy white solid. 4.3 g; 41%. MS, m/z (relative intensity): 362[M−C(CH₃)₃+1H, 100%], 418 [M+1H, 20%].

[0818] (S)-2-((S)-2-Methyl-pentyl)-succinic acid 4-tert-butyl ester and(3S,5S)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123

[0819] To the ester 122 in a mixture of THF (203.0 mL) and water (61.0mL) at 0° C. was added a premixed solution of 30% H₂O₂ (12.2 mL) andLiOH (0.8 M, 42.7 mL). The resulting solution was stirred at 0° C. for 4hours. To the reaction was added sodium bisulfite (7 g), sodium sulfite(13 g), and water (60 mL). A 1:1 mixture of ether/hexane (200 mL) wasthen added and the organic phase was separated. The aqueous phase wasextracted with ether and the combined organic extract was dried overMgSO₄ and concentrated in vacuo. The residue was dissolved in heptaneand let stir for 5 minutes. The resulting precipitate was filtered andthe filtrate was concentrated to dryness to give as an oil.

[0820] (3S,5S)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester123

[0821] A procedure similar to the preparation of(3S,5R)-3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103 wasfollowed giving 123 as an oil. 4.0 g; 76.0%. MS, m/z (relativeintensity): 230 [M−C(CH₃)₃+1H+CH₃CN, 100%], 189 [M−C(CH₃)₃+1H, 70%].

[0822] (3S,5S)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic Acidtert-butyl Ester 124

[0823] A procedure similar to the preparation of(3S,5R)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic acidtert-butyl ester 104 was followed giving 6.9 g of 124. MS, m/z (relativeintensity): 343 [M−C(CH₃)₃+1H, 70%], 384 [M−C(CH₃)₃+1H+CH₃CN, 100%].

[0824] (3S,5S)-3-Azidomethyl-5-methyl-heptanoic acid tert-butyl ester125

[0825] A procedure similar to the preparation of(3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 wasfollowed giving 2.9 g; 66% of 125 as an oil. MS, m/z (relativeintensity): 212 [M−C(CH₃)₃−1H, 45%].

[0826] (3S,5S)-3-Aminomethyl-5-methyl-octanoic Acid tert-butyl Ester 126

[0827] A mixture of 125 (2.8 g, 10.4 mmol) and 10% Pd/C (1.0 g) inmethanol (50.0 mL) was hydrogenated at 41 PSI for 96 hours. The solutionwas filtered to give 1.7 g of crude 126 which was used in the next stepwithout further purification. MS, m/z (relative intensity): 244 [M+1H,100%], 285 [M+1H+CH₃CN, 25%].

Example 11 (3S,5S)-3-Aminomethyl-5-methyl-octanoic Acid

[0828] A procedure similar to the preparation of example 10(3S,5R)-3-aminomethyl-5-methyl-heptanoic acid was followed givingexample 11.380 mg; 29.0%. ¹H NMR (CD₃OD) δ 2.90 (dd, J=3.9, 8.8 Hz, 1H),2.80 (dd, J=7.6, 5.1 Hz, 1H), 2.40 (dd, J=3.2, 12.51 Hz, 1H), 2.20 (dd,J=8.8, 6.8 Hz, 1H), 2.05 (m, 1H), 1.55 (m, 1H), 1.30 (m, 3H), 1.10 (m,2H), 0.85 (m, 6H); MS, m/z (relative intensity): 187 [M+1H, 100%), 211[M+1H+CH₃CN, 30%].

Example 12 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-heptanoic Acid

[0829]

[0830] (S)-2,6-Dimethyl-oct-2-ene 127

[0831] (R)-(−)-Citronellyl bromide (49.1 g, 224.2 mmol) was dropwiseadded to a solution of LAH 1.0 M in THF (336 mL, 336 mmol) at 0° C. overa 45-minute period. Stirring was continued for an additional 4 hours at0° C. The reaction was slowly quenched with a saturated solution ofammonium chloride followed by the addition of ether (100 mL). Theresulting white slurry was filtered and the filtrate was dried overMgSO₄ The solution was concentrated under reduced pressure to afford26.2 g; 83% of 127 as an oil. MS, m/z (relative intensity): 180[M−1H+CH₃CN, 100%], 139 [M−1H, 90%].

[0832] (S)-4-Methyl-hexanoic acid 128

[0833] A procedure similar to that used to prepare compound 120 was usedgiving 15.9 g of 128 as an oil. MS, m/z (relative intensity): 129 [M−1H,100%], 170 [M−1H+CH₃CN, 70%].

[0834](4R,5S)-4-Methyl-3-((S)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one 129

[0835] A procedure similar to that used to prepare(4R,5S)-4-Methyl-3-((S)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one121 was used giving 35.0 g of crude(4R,5S)-4-methyl-3-((S)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one 129as an oil. It was used in the next step without further purification.MS, m/z (relative intensity): 290 [M+1H, 100%], 331 [M+1H+CH₃CN, 20%].

[0836](3S,5S)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-heptanoicAcid Tert-Butyl Ester 130

[0837] A procedure similar to that used to prepare(3S,5S)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester 122 was used to give 4.6.0 g, 25.4% of 130 as awhite solid. MS, m/z (relative intensity): 348 [M−C(CH₃)₃+1H, 100%], 443[M−1H+CH₃CN, 100%], 402 [M−1H, 55%], 404 [M+1H, 45%].

[0838] (3S,5S)-3-Hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester131

[0839] A procedure similar to that used to prepare(3S,5S)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123 wasgiving 1.2 g, 52.1% of 131 as an oil. MS, m/z (relative intensity): 175[M−C(CH₃)₃+1H, 100%], 173 [M−C(CH₃)₃-1H, 100%], 216 [M−C(CH₃)₃+1H+CH₃CN,95%].

[0840] (3S,5S)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-heptanoic Acidtert-butyl Ester 132

[0841] A procedure similar to the preparation of(3S,5R)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic acidtert-butyl ester 104 was followed giving 2.1 g of 132 as an oil. Theproduct was used in the next step without further purification. MS, m/z(relative intensity): 329 [M−C(CH₃)₃+1H, 85%], 370 [M−C(CH₃)₃+1H+CH₃CN,65%].

[0842] (3S,5S)-3-Azidomethyl-5-methyl-heptanoic acid tert-butyl ester133

[0843] A procedure similar to the preparation of(3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 wasfollowed giving 0.76 g, 54.0% of 133 as an oil. MS, m/z (relativeintensity): 198 [M−C(CH₃)₃−1H, 100%]

[0844] (3S,5S)-3-Aminomethyl-5-methyl-heptanoic acid tert-butyl ester134

[0845] A procedure similar to that used for(3S,5S)-3-aminomethyl-5-methyl-octanoic acid tert-butyl ester 126 wasused giving 0.62 g of 134 as an oil. The product was used in the nextstep without further purification. MS, m/z (relative intensity): 230[M+1H, 100%], 271 [M+1H+CH₃CN, 45%].

Example 12 (3S,5S)-3-Aminomethyl-5-methyl-heptanoic Acid

[0846] A procedure similar to that used for Example 11 was used giving(3S,5S)-3-aminomethyl-5-methyl-heptanoic acid (0.3 g, 65.1%) as a whitesolid. ¹H NMR (CD₃OD) δ 2.80-3.00 (m, 2H), 2.40 (m, 1H), 2.20 (dd,J=8.2, 7.1 Hz, 1H), 2.05 (m, 1H), 1.30-1.50 (m, 3H), 1.00-1.20 (m, 2H),0.9 (m, 6H); MS, m/z (relative intensity): 187 [M+1H, 100%], 211[M+1H+CH₃CN, 30%]. MS, m/z (relative intensity): 174 [M+1H, 100%], 172[M−1H, 100%], 215 [M+1H+CH₃CN, 20%].

Example 13 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-nonanoic AcidHydrochloride

[0847]

[0848] (R)-4-Methyl-octanoic acid 136

[0849] Lithium chloride (0.39 g, 9.12 mmol) and copper (I) chloride(0.61 g, 4.56 mmol) were combined in 45 ml THF at ambient temperatureand stirred 15 minutes, then cooled to 0° C. at which timeethylmagnesium bromide (1 M solution in THF, 45 mL, 45 mmol) was added.(S)-citronellyl bromide (5.0 g, 22.8 mmol) was added dropwise and thesolution was allowed to warm slowly to ambient temperature with stirringovernight. The reaction was quenched by cautious addition of sat. NH₄Cl(aq), and stirred with Et₂O and sat. NH₄Cl (aq) for 30 minutes. Thephases were separated and the organic phase dried (MgSO₄) andconcentrated. The crude product was used without purification.

[0850] To a solution of alkene 135 (3.8 g, 22.8 mmol) in 50 mL acetoneat 0° C. was added Jones' reagent (2.7 M in H₂SO₄ (aq), 40 mL, 108 mmol)and the solution was allowed to warm slowly to ambient temperature withstirring overnight. The mixture was partitioned between Et₂O and H₂O,the phases were separated, and the organic phase washed with brine,dried (MgSO₄), and concentrated. The residue was purified by flashchromatography (8:1 hexanes:EtOAc) to afford 2.14 g (59%) of acid 136 asa colorless oil: LRMS: m/z 156.9 (M+); ¹H NMR (CDCl₃): δ 2.33 (m, 2H),1.66 (m, 1H), 1.43 (m, 2H), 1.23 (m, 5H), 1.10 (m, 1H), 0.86 (m, 6H).Jones' reagent was prepared as a 2.7M solution by combining 2⁶⁰.7 gCrO₃, 23 mL H₂SO₄, and diluting to 100 mL with H₂O.

[0851] (4R,5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one 137

[0852] To acid 136 (2.14 g, 13.5 mmol) in 25 mL CH₂Cl₂ at 0° C. wasadded 3 drops DMF, followed by oxalyl chloride (1.42 mL, 16.2 mmol)resulting in vigorous gas evolution. The solution was warmed directly toambient temperature, stirred 30 minutes, and concentrated. Meanwhile, toa solution of the oxazolidinone (2.64 g, 14.9 mmol) in 40 mL THF at −78°C. was added n-butyllithium (1.6 M soln in hexanes, 9.3 mL, 14.9 mmol)dropwise. The mixture was stirred for 10 minutes at which time the acidchloride in 10 mL THF was added dropwise. The reaction was stirred 30minutes at −78° C., then warmed directly to ambient temperature andquenched with sat. NH4Cl. The mixture was partitioned between Et₂O andsat. NH₄Cl (aq), the phases were separated, and the organic phase dried(MgSO₄), and concentrated to furnish 3.2 g of oxazolidinone 137 as acolorless oil. LRMS: m/z 318.2 (M+); ¹H NMR (CDCl₃): δ 7.34 (m, 5H),5.64 (d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 2.96 (m, 1H), 2.86(m, 1H), 1.66 (m, 1H), 1.47 (m, 2H), 1.26 (m, 5H), 1.13 (m, 1H), 0.88(m, 9H). The crude product was used without purification.

[0853](3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-nonanoicacid tert-butyl ester 138

[0854] To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mLTHF at −78° C. was added n-butyllithium (1.6 M soln in hexanes, 7.6 mL,12.1 mmol), and the mixture stirred 10 minutes at which timeoxazolidinone 137 (3.2 g, 10.1 mmol) in 10 mL THF was added dropwise.The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL,12.1 mmol) was added quickly dropwise at −50° C., and the mixture wasallowed to warm slowly to 10° C. over 3 hours. The mixture waspartitioned between Et₂O and sat. NH₄Cl (aq), the phases were separated,and the organic phase dried (MgSO₄), and concentrated. The residue waspurified by flash chromatography (16:1 to 8:1 hexanes:EtOAc) to provide2.65 g (61%) of ester 138 as a colorless crystalline solid, mp=84-86° C.[α]_(D) ²³+17.1 (c=1.00, CHCl₃); ¹H NMR (CDCl₃): δ 7.34 (m, 5H), 5.62(d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd,J=9.8, 16.4 Hz, 1H), 2.40 (dd, J=5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38(s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H); ¹³C NMR (CDCl₃) δ176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33,40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36,14.26. Anal. Calcd for C₂₅H₃₇NO₅: C, 69.58; H, 8.64; N, 3.25. Found: C,69.37; H, 8.68; N, 3.05.

[0855] (S)-2-((R)-2-Methyl-hexyl)-succinic acid 4-tert-butyl ester 139

[0856] To a solution of ester 138 (2.65 g, 6.14 mmol) in 20 mL THF at 0°C. was added a precooled (0° C.) solution of LiOH monohydrate (1.0 g,23.8 mmol) and hydrogen peroxide (30 wt % aqueous soln, 5.0 mL) in 10 mLH₂O. The mixture was stirred vigorously for 90 minutes, then warmed toambient temperature and stirred 90 minutes. The reaction was quenched at0° C. by addition of 100 mL 10% NaHSO₃ (aq), then extracted with Et₂O.The phases were separated, and the organic phase washed with brine,dried (MgSO₄), and concentrated. The crude acid 139 was used withoutpurification.

[0857] (3S,5R)-3-Hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester140

[0858] To a solution of the crude acid 139 (6.14 mmol) in 30 mL THF at0° C. was added borane-dimethyl sulfide complex (2.0 M soln in THF, 4.6mL, 9.2 mmol), and the mixture was allowed to warm slowly to ambienttemperature overnight. Additional BH₃-DMS was added until the acid wascompletely consumed (ca. 5 mL). The reaction was quenched by addition ofMeOH, then partitioned between Et₂O and sat. NaHCO₃ (aq). The phaseswere separated, and the organic phase washed with brine, dried (MgSO₄),and concentrated to provide alcohol 140. LRMS: m/z 226.1; ¹H NMR(CDCl₃): δ 3.63 (dd, J=11.0, 4.2 Hz, 1H), 3.42 (dd, J=11.0, 6.8 Hz, 1H),2.30 (dd, J=14.9, 7.6 Hz, 1H), 2.20 (dd, J=14.9, 5.6 Hz, 1H), 2.03 (m,2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 (m, 2H), 0.85 (m, 6H). The crudeproduct was used without purification.

[0859] (3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-nonanoic acidtert-butyl ester 141

[0860] To alcohol 140 (6.14 mmol) in 30 mL CH₂Cl₂ at 0° C. was addedDMAP (0.1 g), p-toluenesulfonyl chloride (1.37 g, 7.2 mmol), and thentriethylamine (1.8 mL, 13 mmol) was added quickly dropwise. The mixturewas warmed immediately to ambient temperature following addition andstirred overnight, and did not proceed to completion. The mixture waspartitioned between Et₂O and 1N HCl (aq), the phases were separated, andthe organic phase washed with sat. NaHCO₃ (aq), dried (MgSO₄), andconcentrated to provide tosylate 141. The product was used withoutfurther purification.

[0861] (3S,5R)-3-Azidomethyl-5-methyl-nonanoic acid tert-butyl ester 142

[0862] A procedure similar to the preparation of(3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 wasfollowed giving azide 142 as a colorless oil. LRMS: m/z 200.1; ¹H NMR(CDCl₃): δ 3.31 (dd, J=12.2, 4.2 Hz, 1H), 3.19 (dd, J=12.2, 5.9 Hz, 1H),2.22 (m, 1H), 2.10 (m, 1H), 1.39 (s, 9H), 1.21 (m, 8H), 1.00 (m, 2H),0.81 (m, 6H).

Example 13 (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid hydrochloride

[0863] The azide 142 (1.0 g) was hydrogenated in the presence of 20%Pd/C, EtOH, at 45 psi of H₂ for 15 hours to provide the crude aminoester 143 which was concentrated and used without purification. To theamino ester 143 was added 6 mL 6N HCl (aq) and the mixture was heated toreflux 90 minutes, cooled, and concentrated. Recrystallization fromEtOAc:hexanes provided 0.38 g (45% from azide) of(3S,5R)-3-aminomethyl-5-methyl-nonanoic acid hydrochloride as acolorless crystalline solid (HCl salt), and a second crop of 82 mg (10%from azide) was also obtained. mp=146-156° C. LRMS: m/z 200.1 (M+); ¹HNMR (CDCl₃): δ 2.87 (dd, J=13.2, 5.4 Hz, 1H), 2.79 (dd, J=13.2, 7.3 Hz,1H), 2.29 (d, J=6.8 Hz, 2H), 2.08 (m, 1H), 1.31 (m, 1H), 1.09 (m, 7H0,0.92 (m, 1H), 0.68 (m, 6H). Anal. Calcd for C₁₁H₂₄NO₂Cl: C, 55.57; H,10.17; N, 5.89. Found: C, 55.69; H, 10.10; N, 5.86.

Example 14 Synthesis of (3S, 5S)-3-Aminomethyl-5-methyl-nonanoic Acid

[0864]

[0865] The (S)-acid 145 was prepared from (R)-citronellyl bromideaccording to the procedure outlined above for (R)-4-methyl-octanoic acid136. The yield was comparable and the ¹H NMR spectrum was identical tothat of the (R)-acid enantiomer. LRMS: m/z 158.9 (M+1).

[0866] Oxazolidinone 146 was prepared from acid 145 as described abovefor (4R,5S)-4-methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one 137.

[0867] LRMS: m/z 290.1 (M−27); ¹H NMR (CDCl₃): δ 7.38 (m, 3H), 7.28 (m,2H), 5.64 (d, J=7.1 Hz, 1H), 4.74 (quint, J=6.8 Hz, 1H), 2.92 (m, 2H),1.71 (m, 1H), 1.42 (m, 7H), 1.18 (m, 1H), 0.88 (m, 9H).

[0868] t-Butyl ester 147 was prepared from oxazolidinone 146 asdescribed above for compound 138. LRMS: m/z 348.1 (M-83).

[0869] Alcohol 149 was prepared from the t-butyl ester 147 as describedabove for (3S,5R)-3-hydroxymethyl-5-methyl-nonanoic acid tert-butylester 140. LRMS: m/z 156.9 (M−100); ¹H NMR (CDCl₃): δ 3.60 (dd, J=11.0,4.6 Hz, 1H), 3.45 (dd, J=11.0, 6.8 Hz, 1H), 2.24 (m, 2H), 2.04 (m, 2H),1.42 (s, 9H), 1.17-1.38 (m, 7H), 1.11 (m, 1H), 0.84 (m, 6H).

Example 14 (3S, 5S)-3-Aminomethyl-5-methyl-nonanoic Acid

[0870] (3S, 5S)-3-Aminomethyl-5-methyl-nonanoic acid was obtained from149 as described above for (3S,5R)-3-aminomethyl-5-methyl-nonanoic acidhydrochloride. The crude HCl salt thus obtained was purified by ionexchange chromatography on Dowex 50WX8 50-100 mesh, H-Form resin, using10% NH₄OH as eluant to provide the free base. The waxy solid was washedtwice with Et₂O and dried to furnish an amorphous white solid, mp144-146° C. LRMS: m/z 172.0 (M−28); ¹H NMR (CDCl₃): δ 2.76 (d, J=5.9 Hz,2H), 2.14 (m, 1H), 1.96 (m, 2H), 1.25 (m, 1H), 1.12 (m, 6H), 0.96 (m,2H), 0.66 (m, 6H).

Example 15 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-decanoic Acid

[0871]

[0872] (R)-2,6-Dimethylundec-2-ene 153

[0873] A procedure similar to the preparation of(S)-2,6-dimethyl-non-2-ene 119 was used giving 153 as a colorless oil(20.16 g, 98%). ¹H NMR (400 MHz, CDCl₃) δ 5.10-5.06 (m, 1H), 2.10-1.89(m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.34-1.23 (m, 4H), 1.15-1.06 (m,2H), 0.88-0.81 (m, 11H).

[0874] (R)-4-methylnonanoic acid 154

[0875] (R)-2,6-Dimethylundec-2-ene 153 (10.03 g, 55.03 mmol) wasdissolved in acetone (270 mL) and cooled to 0° C. Jones reagent(CrO₃/H₂SO₄) (2.7 M, 120 mL) was added dropwise, and the reactionallowed to warm to room temperature over 18 hours. The reaction waspoured on to water/Na₂SO₄ (200 mL), and the aqueous layer extracted withethyl acetate (4×100 mL). The combined organics were dried over MgSO₄,filtered and rotovapped to give an oil. The crude oil was dissolved inCH₂Cl₂ (400 mL) and cooled to −78° C. Ozone was bubbled into reactionuntil blue to remove traces of the impurity(6E)(3S)-3,7-dimethylocta-1,6-diene. Dimethylsulfide (5 mL) was added,and the reaction stirred at room temperature for 2 hours. The solventwas removed, and the crude material chromatographed on silica elutingwith 20% EtOAc/hex to give oil. The oil was dissolved in ether (100 mL)and extracted with 10% NaOH (2×25 mL). The aqueous layers were combinedand extracted with ether (50 mL). The aqueous layer was cooled to 0° C.and acidified with HCl. The acidic layer was extracted with EtOAc (3×100mL), and the combined extracts dried over MgSO₄, filtered and rotovappedto give 154 as an oil (6.86 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ 2.40-2.25(m, 4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H);[α]_(D)=−11.4 (c1 in CHCl₃).

[0876](4R,5S)-4-Methyl-3-((R)-4-methyl-nonanoyl)-5-phenyl-oxazolidin-2-one 155

[0877] Compound 154 (6.504 g, 37.76 mmol) was dissolved in THF (95 mL)and cooled to 0° C. Triethylamine (19.74 mL, 141.6 mmol) was addeddropwise, followed by dropwise addition of trimethylacetyl chloride(6.98 mL, 56.64 mmol). The thick white suspension was stirred at 0° C.for 90 minutes. LiCl (1.86 g, 41.54 mmol),(4R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one (6.824 g, 38.51 mmol), andTHF (70 mL) were added, and the reaction warmed to room temperatureovernight. The solvent was evaporated. The solids were taken up inEtOAc, filtered off, and washed generously with EtOAc. The filtrate waswashed with water (2×50 mL), and brine. The organics were dried overMgSO₄, filtered, and rotovapped. The crude material was chromatographedon silica eluting with 10% EtOAc/hexanes to give 155 as an oil (10.974g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.35 (m, 3H), 7.31-7.26 (m, 2H),5.66 (d, J=7.33 Hz, 1H), 4.76 (quin, J=7.03 Hz, 1H), 3.04-2.96 (m, 1H),2.93-2.86 (m, 1H), 1.74-1.66 (m, 1H), 1.52-1.47 (m, 1H), 1.46-1.36 (m,2H), 1.27-1.16 (m, 2H), 0.92-0.87 (m, 8H); [α]_(D)=+34.1 (c1 in CHCl₃).

[0878](3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-decanoicacid tert-butyl ester 156

[0879] A procedure similar to the preparation of(3S,5S)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester 122 was followed giving(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-decanoicacid tert-butyl ester 156 as an oil (0.668 g, 90%). ¹H NMR (400 MHz,CDCl₃) δ 7.41-7.28 (m, 5H), 5.63 (d, J=7.33 Hz, 1H), 4.74 (quin, J=6.84Hz, 1H), 4.33-4.26 (m, 1H), 2.68 (dd, J=16.4, 9.77 Hz, 1H), 2.41 (dd,J=16.6, 4.88 Hz, 1H), 1.68 (quin, J=6.6 Hz, 1H), 1.50-1.32 (m, 10H),1.28-1.21 (m, 1H), 1.15-1.08 (m, 1H), 0.90-0.86 (m, 9H); MS (APCI) m/z348 (M+-97, 100%); [α]_(D)=+18.8 (c1 in CHCl₃).

[0880] (S)-2-((R)-2-Methyl-heptyl)-succinic acid 4-tert-butyl ester 157

[0881] Compound 156 (5.608 b, 12.59 mmol) was dissolved in THF/H₂O (60mL/14 mL) and cooled to 0° C. LiOH (1N, 18.89 mL) and H₂O₂ (35%, 4.45μL, 50.4 mmol) were combined, and then added to the reaction dropwisekeeping T<5° C. the reaction was stirred at 0° C. for 4 hours, andquenched with Na₂SO₃ (6.3 g) and NaHSO₃ (3.4 g) in 50 mL H₂O addeddropwise. The reaction was stirred for 15 minutes, and the layersseparated. The aqueous layer was extracted with EtOAc (3×100 mL), andthe combined extracts dried over MgSO₄, filtered, and rotovapped to givean oil. The crude material was dissolved in EtOAc (10 mL) and addeddropwise to heptane (250 mL). The suspension was stirred for 20 minutes,and the solids filtered and washed with heptane. The filtrate was washedwith 60° C. H₂O (100 mL), dried over MgSO₄, filtered, and rotovapped togive 157 as an oil (3.52 g). the material was used directly in the nextstep.

[0882] (3S,5R)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester158

[0883] Compound 157 (3.52 g, 12.3 mmol) was dissolved in anhydrous THF(123 mL) and cooled to 0° C. Borane dimethylsulfide complex (10 M, 3.69mL) was added dropwise, and the reaction then warmed to room temperatureand stirred for 1 hour. the reaction was cooled to 0° C., and quenchedwith MeOH (20 mL) added dropwise. The reaction was stirred for 18 hours,and the solvent rotovapped off. The crude material was chromatographedon silica eluting with 20% EtOAc/hexanes to give 158 (2.28 g, 68%) as anoil. ¹H NMR (400 MHz, CDCl₃) δ 3.65-3.59 (m, 1H), 3.43 (dd, J=11.1, 6.96Hz, 1H), 2.31 (dd, J=14.9, 7.57 Hz, 1H), 2.21 (dd, J=15.1, 5.62 Hz, 1H),2.06-2.02 (m, 1H), 1.43 (s, 9H), 1.40-1.25 (m, 4H), 1.07-1.13 (m, 1H),1.03-0.96 (m, 1H), 0.86-0.84 (m, 6H); MS (APCI) m/z 216 (M⁺-56, 100%).

[0884] (3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acidtert-butyl ester 159

[0885] Compound 158 (2.27 g, 8.33 mmol) was dissolved in CH₂Cl₂ (30 mL)and cooled to 0° C. Tosyl chloride (1.91 g, 10.0 mmol) and catalyticDMAP were added, followed by dropwise addition of triethylamine (2.55mL, 18.33 mmol). The reaction was then stirred at 0° C. for 18 hours.The solvent was rotovapped off (removed under reduced pressure), and thecrude material washed with EtOAc and filtered. The solids were washedwith EtOAc, and the filtrate washed with 0.5N HCl (20 mL), brine (30mL), dried over MgSO₄, filtered and rotovapped. The oil waschromatographed on silica eluting with a 5% EtOAc/hexanes gradient to10% EtOAc/hexanes to give 159 (3.399 g, 96%) as an oil. ¹H NMR (400 MHz,CDCl₃) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30 Hz, 2H), 3.99 (dd,J=9.65, 3.54 Hz, 1H), 3.89 (dd, J=9.52, 5.37 Hz, 1H), 2.42 (s, 3H), 2.28(dd, J=14.7, 6.23 Hz, 1H), 2.19-2.14 (m, 1H), 2.10 (dd, J=14.9, 6.35 Hz,1H), 1.38 (s, 9H), 1.31-1.17 (m, 3H), 1.08-0.81 (m, 2H), 0.79-0.76 (m,6H); [c]D=-10.1 (c1 in CHCl₃).

[0886] (3S,5R)-3-Azidomethyl-5-methyl-decanoic acid tert-butyl ester 160

[0887] Compound 159 (3.01 g, 7.05 mmol), sodium azide (1.26 g, 19.40mmol) and DMSO (12 mL) were combined and heated to 60° C. for 3 hours.EtOAc (100 mL) was added to the reaction and filtered. The solids werewashed with EtOAc (20 mL), and the filtrated evaporated. The crudematerial was chromatographed on silica eluting with 5% EtOAc/hexanes togive 160 as an oil (1.86 g, 89%).

[0888] (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid tert-butyl ester 161

[0889] A solution of compound 160 (1.86 g, 6.25 mmol) in THF (50 mL) wasshaken over 5% Pd/C under hydrogen and pressure for 8 hours with threepurges of hydrogen. The catalyst was filtered off and the filtrateevaportated. The crude material was chromatographed on silica elutingwith methanol to give 161 as an oil (1.21 g, 71%). ¹H NMR (400 MHz,CDCl₃) δ 2.70 (dd, J=12.9, 4.40 Hz, 1H), 2.54 (dd, J=12.7, 6.59 Hz, 1H),2.26 (dd, J=14.5, 6.96, 1H), 2.12 (dd, J=14.5, 6.47 Hz, 1H), 1.91 (m,1H), 1.91 (m, 1H), 1.43 (s, 12H), 1.39-1.25 (m, 4H), 1.14-1.07 (m, 1H),1.03-0.97 (m, 1H), 0.86-0.82 (m, 6H).

Example 15 (3S,5R)-3-Aminomethyl-5-methyl-decanoic Acid

[0890] Compound 161 (1.20 g, 4.44 mmol) was heated to 50° C. in 3N HCl(30 mL) for 4 hours. The solvent was evaporated, and the oil washed withtoluene, and evaporated. The crude material was passed through an ionexchange column (Dowex 50WX8-100, strongly acidic) eluting with water,then 0.5N NH₄OH. Isolate (3S,5R)-3-aminomethyl-5-methyl-decanoic acid asa white solid (0.725 g, 75%): mp=174-175° C.; ¹H NMR (400 MHz, CDCl₃) δ2.83 (dd, J=12.69, 4.88 Hz, 1H), 2.70 (dd, J=13.1, 7.45 Hz, 1H), 2.08(d, J=6.59 Hz, 2H), 1.98 (m, 1H), 1.28-1.20 (m, 1H), 1.19-1.09 (m, 2H),0.99-0.91 (m, 2H), 0.66 (m, 6H); MS (APCI) m/z 215 (M+, 10%), 174(M+-41, 100%); [α]_(D)=−5.7 (c1.025 in H₂O).

Example 16 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-decanoic Acid

[0891]

[0892] (S)-2,6-Dimethyl-undec-2-ene 162

[0893] nPropylmagnesium chloride/ether solution (2.0 M, 228 mL) wascooled to 5-20° C. under a N₂ atmosphere. LiCl (3.87 g, 91.25 mmol),CuCl₂ (6.13 g, 45.63 mmol), and distilled THF (456 mL) were combined andstirred for 30 minutes. The Li₂CuCl₄ solution was added via cannula tothe Grignard reagent, and the resulting solution stirred for 30 minutesat −20° C. R-(−)-Citronellyl bromide (50 g, 228.1 mmol) was dissolved inTHF (60 mL) and added dropwise to the Grignard solution. The reactionwas stirred at 0° C. for 1 hour. The reaction was cooled to −40° C. andquenched with NH₄Cl (sat'd, 200 mL) added dropwise. The layers wereseparated and the aqueous layer extracted with ether (3×100 mL). Thecombined organics were dried over MgSO₄, filtered, and rotovapped togive an oil. The crude material was chromatographed on silica elutingwith hexanes to give 162 as a colorless oil (9.15 g, 22%). ¹H NMR (400MHz, CDCl₃) δ 5.10-5.06 (m, 1H), 2.10-1.89 (m, 2H), 1.66 (s, 3H), 1.58(s, 3H), 1.34-1.23 (m, 4H), 1.15-1.06 (m, 2H), 0.88-0.81 (m, 1H).

[0894] (S)-4-Methylnonanoic Acid 163

[0895] Compound 162 (7.97 g, 43.7 mmol) was dissolved in acetone (214mL) and cooled to 0° C. Jones reagent (CrO₃/H₂SO₄) (2.7 M, 95 mL) wasadded dropwise, and the reaction allowed to warm to room temperatureover 18 hours. The reaction was poured on to water/Na₂SO₄ (200 mL), andthe aqueous layer extracted with ethyl acetate (4×100 mL). The combinedorganics were dried over MgSO₄, filtered, and rotovapped to give an oil.The crude oil was chromatographed on silica eluting with hexanes to give163 as an oil (5.56 g, 74%). ¹H NMR (400 MHz, CDCl₃) δ 2.40-2.25 (m,4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H); MS APCIm/z 170.9 (M−1, 100%).

[0896](4R,5S)-4-Methyl-3-((S)-4-methyl-nonanoyl)-5-phenyl-oxazolidin-2-one 164

[0897] A procedure similar to that used to prepare compound 155 was usedexcept that (S)-4-methylnonanoic acid 163 (5.56 g, 32.27 mmol) was usedas a reactant to give 164 as an oil (10.70 g 100%). ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.34 (m, 3H), 7.28 (d, J=6.59 Hz, 2H), 5.64 (d, J=7.33 Hz,1H), 4.74 (quin, J=6.78 Hz, 1H), 2.94-2.85 (m, 2H), 1.73-1.67 (m, 1H),1.47-1.43 (m, 1H), 1.39-1.22 (m, 7H), 0.90-0.84 (m, 8H).

[0898](3S,5S)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-decanoicAcid tert-butyl Ester 165

[0899] A procedure similar to that used to prepare compound 156 was usedto give 165 as a solid (4.25 g, 61%). MS (APCI) m/z 446 (M⁺+1, 10%), 390(M+-55, 100%, -tBu).

[0900] (S)-2-((S)-2-Methyl-heptyl)-succinic acid 4-tert-butyl ester 166

[0901] A procedure similar to that used for compound 157 was used exceptthat ester 165 (8.42 g, 18.89 mmol) was used as a reactant to give 166as an oil (5.81 g). The material was used directly in the next step. MS(APCI) m/z 285 (M−1, 100%).

[0902] (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester167

[0903] A procedure similar to that used to prepare compound 158 was usedexcept that (S)-2-((S)-2-methyl-heptyl)-succinic acid 4-tert-butyl ester166 (5.78 g, 20.18 mmol) was used as a reactant to give 167 as an oil(4.18 g, 76%). ¹H NMR (400 MHz, CDCl₃) δ 3.64-3.58 (m, 1H), 3.84-3.42(m, 1H), 2.28-2.20 (m, 1H), 2.09-2.02 (m, 1H), 1.43 (s, 9H), 1.26-1.18(m, 8H), 1.11-1.04 (m, 2H), 0.87-0.83 (m, 6H); MS (APCI) m/z 217 (M+-55,50%, -tBu).

[0904] (3S,5S)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acidtert-butyl ester 168

[0905] A procedure similar to that used to prepare compound 159 was usedexcept that (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butylester 167 (4.164 g, 15.29 mmol) was used as a reactant to give 168 as anoil (4.17 g, 64%).

[0906]¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30Hz, 2H), 3.97 (dd, J=9.52, 4.15 Hz, 1H), 3.90 (dd, J=9.52, 5.13 Hz, 1H),2.42 (s, 3H), 2.28, 2.19-2.13 (m, 2H), 1.37 (s, 9H), 1.27-1.01 (m, 11H),0.85 (t, J=7.08 Hz, 3H), 0.76 (d, J=6.35 Hz, 3H).

[0907] (3S,5S)-3-Azidomethyl-5-methyl-decanoic acid tert-butyl ester 169

[0908] A procedure similar to that used to prepare compound 160 was usedexcept (3S,5S)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acidtert-butyl ester 168 (4.155 g, 9.74 mmol) was used as a reactant to give169 as an oil (2.77 g, 96%). MS (APCI) m/z 270 (M⁺−27, 30%, —N₂), 214(M+-87, 100%, -tBu, —N₂).

[0909] (3S,5S)-3-Aminomethyl-5-methyl-decanoic acid tert-butyl ester 170

[0910] A procedure similar to that used to prepare compound 161 was usedexcept that (3S,5S)-3-Azidomethyl-5-methyl-decanoic acid tert-butylester 169 (2.50 g, 8.405 mmol) was used as a reactant to give 170 as anoil (1.648 g, 72%). MS (APCI) m/z 272 (M⁺+1, 100%).

Example 14 (3S,5S)-3-Aminomethyl-5-methyl-decanoic Acid

[0911] A procedure similar to that used for Example 15 was used excepttert-butyl (3S,5S)-3-(aminomethyl)-5-methyldecanoate 170 (1.6 g, 6.00mmol) was used as a reactant to give Example 16 as a white solid (72%).MS (APCI) m/z 272 (M⁺+1, 100%). mp=174-175° C.; ¹H NMR (400 MHz, CD₃OD)δ 2.91 (dd, J=12.9, 3.91 Hz, 1H), 2.83 (dd, J=12.7, 7.57 Hz, 1H), 2.43(dd, J=15.6, 3.17 Hz, 1H), 2.19 (dd, J=15.6, 8.80 Hz, 1H), 2.08-2.04 (m,1H), 1.53 (m, 1H), 1.38-1.27 (m, 7H), 1.78-1.03 (m, 2H), 0.90-0.86 (m,6H), 0.66 (m, 6H); MS (APCI) m/z 216 (M⁺+1, 100%), 214 (M−1, 100%);[α]_(D)=+21.4 (cl in MeOH).

Example 17 Synthesis of (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic Acid

[0912]

[0913] (S)-2-Benzyl-3-methyl-butan-1-ol 172

[0914] Ref. JACS 1997;119:6510. Amide 171.

[0915] Large Scale Procedure for the Synthesis of Acetic Acid(S)-2-benzyl-3-methyl-butyl ester 173 from 171

[0916] A of n-butyl lithium (10 M in hexane, 100 mL, 1000 mmol, 3.9equiv.) was added to a solution of diisopropylamine (108.9 g, 150.9 mL,1.076 mol, 4.20 equiv.) in THF (600 mL), at −78° C. The resultingsolution was stirred for 10 minutes and warmed to 0° C., and hold at thetemperature for 10 minutes. Borane-ammonia complex (31.65 g, 1.025 mmol,and 4.0 equiv) was added in one portion, and the suspension was stirredat 0° C. for 15 minutes, and at 23° C. for 15 minutes, and then cooledto 0° C. A solution of amide 171 (86 g, 256.41 mmol, 1 equiv.) in THFwas added to the cold hydride via a cannula over 3 minutes. The reactionwas stirred at 23° C. for overnight, then cooled to 0° C. Excess hydridewas quenched by the slow addition of 3N HCl (700 mL). The reactionmixture was diluted with more aqueous HCl (3N, 200 mL), and brine andthen extracted with ether (4×15 mL). The ether solution was concentratedto a small volume, and 200 mL 2N NaOH was added, and stirred at 23° C.for 2.5 hours. More ether was added and the layers were separated. Theaqueous layer was saturated with salt and extracted with ether (3×200mL). The combined organic was washed with brine and dried on sodiumsulfate. The residue was flash chromatographed (Pet. ether-25% ether-TEA) to give alcohol 172, 50 g. NMR (CDCl₃) δ 7.35-7.16 (m, 5H, C₆H₅),3.55 (app. t, 2H, —CH₂OH), 2.71 (dd, 1H, ArCH₂CH—), 2.52 (dd, 1H,ArCH₂CH), 1.87 (m, 1H, CHCH(Me), 1.67 (m, 1H, CH(Me)₂), 0.98 (d, 3H,CH₃) and 0.96 (d, 3H, CH₃).

[0917] A sample 3.3 g was saved for characterization and the rest wasimmediately acetylated (triethylamine 50 mL, DMAP 4.6 g, acetic acidanhydride 32 mL) overnight at room temperature. Work up followed bychromatography on silica gel eluted with pet ether and then 10% ether inpet ether gave 62 g of 173.

[0918] NMR (CDCl₃) δ 7.30-7.14 (m, 5H, C₆H₅), 3.98 (m, 2H, —CH₂OAc),2.71 (dd, 1H, ArCH₂CH—), 2.51 (dd, 1H, ArCH₂CH), 1.99 (s, 3H, CH₃C═O),1.82 (m, 1H, CHCH(Me) and CH(Me)₂), 0.97 (d, 3H, CH₃) and 0.95 (d, 3H,CH₃).

[0919] (S)-Acetoxymethyl-4-methyl-pentanoic acid 174 and(S)-4-Isopropyl-dihydro-furan-2-one 175

[0920] Acetate 173 (15 g, 68.18 mmol) was dissolved in CH₃CN (150 mL),carbon tetrachloride (150 mL) and HPLC grade water (300 mL) and stirred.Sodium periodate (262.50 g, 1220 mmol) was added followed by rutheniumchloride (650 mg, 3.136 mmol). After overnight stirring it was dilutedwith ether and water, and filtered through a pad of Celite. The organicportion was separated and the aqueous phase was further extracted withether. After drying on magnesium sulfate the solvent was evaporated.Potassium carbonate (42 g) was added to the residue and refluxedovernight in methanol (250 mL) and cooled to room temperature. Afterevaporation, water was added to dissolve the solid, and conc. HCl wasadded to bring the pH to 2. Chloroform was added and extractedovernight. The organic phase was separated, and aqueous was furtherextracted with chloroform. The combined organic extracts were dried,evaporated, and the product was purified on a silica gel column and thecompound was eluted with 20% ether in methylene chloride. Fractions weremonitored by tlc, and spots were detected with I₂/KI solution. Fractionswere combined to give 4.6 g of lactone 175. NMR (CDCl₃) δ 4.38 (dd, 1H,CHaHbO), 3.93 (app. t, 1H, CH_(a)H_(b)O), 2.54 (dd, 1H, CH_(c)H_(d)C═O), 2.23 (m, 2H, CHCH(Me) and CHcHd C═O), 1.60 (m, 1H, CH(Me)₂), 0.92(d, 3H, CH₃) and 0.85 (d, 3H, CH₃).

[0921] (3R,4R)-3-Benzyl-4-isopropyl-dihydro-furan-2-one 176

[0922] Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 92 mL,92 mmol) was added in 3-5 minutes to a solution of(S)-β-(2-propyl)-γ-butyrolactone 175 (11.68 g, 91.25 mmol) in dry THF100 mL at −78° C. under argon atmosphere. It was stirred for 1 h and asolution of benzyl iodide (21.87 g, 100.37 mmol) in dry THF was addedrapidly. Stirring was continued for 1.5 hours and quenched at −78° C. bythe addition of a solution of brine followed by ethyl acetate. Theorganic phase was separated and the aqueous was further extracted withether. Chromatography on silica gel first eluted with 5% methylenechloride in pet ether, and finally with 10% ether in pet ether gavedesired compound 11.6 g, 58%. NMR (CDCl₃) δ 7.19 (m, 5H, C₆H₅), 4.02(app. t, 1H, CH_(a)H_(b)O), 3.87 (dd, 1H, CH_(a)H_(b)O), 2.98 (d, 2H,ArCH₂), 2.57 (q, 1H, BnCHC═O), 2.05 (m, 1H, CHCH(Me)₂, 1.55 (m, 1H,CH(Me)₂), 0.81 (d, 3H, CH₃) and 0.72 (d, 3H, CH₃).

[0923] (2R,3R)-2-Benzyl-3-bromomethyl-4-methyl-pentanoic acid EthylEster 177

[0924] Lactone 176 (6.5 g, 29.8 mmol) was dissolved in abs. ethanol (80mL) and cooled in ice bath. Anhydrous HBr was bubbled through thesolution for 1 hour and stirred at room temperature overnight whilemaintaining reaction under dry atmosphere. It was poured onto ice cooledmixture of pet ether and brine. The organic phase was separated, and theaqueous was further extracted with pet ether. The combined organicsolution was washed repeatedly with cold water and dried. Solvent wasremoved in vacuo to give crude compound 7.0 g. NMR (CDCl₃) δ 7.27 (m,5H, C₆H₅), 4.02 (m, 2H, CH₃CH₂O), 3.70 (dd, 1H, CHaHbBr), 3.55 (dd, 1H,CHaHbBr), 2.97 (m, 2H, ArCH₂), 2.83 (q, 1H, BnCHC═O), 2.11 (m, 1H,CHCH(Me)₂, 1.97 (m, 1H, CH(Me)₂), 1.10 (t, 3H, CH₃CH₂O), 0.96 (d, 3H,CH₃) and 0.93 (d, 3H, CH₃).

[0925] (2R,3R)-2-Benzyl-3,4-dimethyl-pentanoic acid ethyl ester 178

[0926] Bromoester 177 (7.25 g, about 80% pure), in ethanol (100 mL)containing triethylamine (3.2 mL) was hydrogenated overnight in thepresence of 20% Pd/C (1.0 g). It was filtered through a pad of Celite,and the cake was washed with ethanol. Solvent was evaporated, and theresidue was taken up in ether, whereupon solid (Et₃N.HCl) separated. Thesolid was removed by filtration. The filtrate was concentrated, and theprocedure was repeated to eliminate all hydrochloride salt. Product waschromatographed on a silica gel column which was eluted with pet etherto give the desired debrominated compound 3.35 g.

[0927] NMR (CDCl₃) δ 7.21 (m, 5H, C₆H₅), 3.95 (m, 2H, CH₃CH₂O), 2.85 (m,2H, ArCH₂), 2.64 (q, 1H, BnCHC═O), 1.85 (m, 1H, CHCH(Me)₂, 1.62 (m, 1H,CH(Me)₂), 1.05 (t, 3H, CH₃CH₂O), 0.95 (d, 3H, CH₃) 0.84 (d, 3H, CH₃) and0.82 (d, 3H, CH₃). MS gave 290 (M+CH₃CN), 249 (M+1), and others at 203.Further elution with ether gave lactone (2.25 g) that was carried overfrom previous step.

[0928] Acetic Acid (2R,3R)-2-benzyl-3,4-dimethyl-pentyl-ester 179

[0929] Ethyl ester 178 (3.20 g, 12.85 mmol) was dissolved in anhydrousether and cooled in ice bath under inert atmosphere. Lithium aluminumhydride (500 mg, 13.15 mmol) was added, and the suspension was stirredat room temperature overnight. Excess LAH was destroyed by carefuladdition of ethyl acetate while the reaction was stirred in ice bath.Saturated sodium sulfate was added cautiously to coagulate the aluminathat separated at room temperature as white precipitate. The reactionmixture was diluted with methylene chloride, and anhydrous sodiumsulfate was added to dry the mixture. After filtration the solution wasconcentrated to give an oil 3.0 g.

[0930] The material (3.0 g) was dissolved in dichloromethane (30 mL) andtriethylamine (2.5 mL), DMAP (200 mg), and acetic anhydride (1.5 mL)were added. It was stirred at room temperature for 3 hours, and dilutedwith ether. The ether solution was washed with waster, 1N HCl, saturatedsodium bicarbonate, brine and dried. The solution was concentrated invacuo to give the acetoxy compound 179 3.16 g. NMR (CDCl₃) δ 7.19 (m,5H, C₆H₅), 4.03 (m, 2H, CH₃CH₂O), 2.69 (m, 2H, ArCH₂), 2.09 (m, 1H,BnCHCH₂O), 2.02 (s, 3H, CH₃C═O), 1.68 (m, 1H, CH₃CHCH(Me)₂, 1.23 (m, 1H,CH(Me)₂), 0.87 (d, 3H, CH₃), 0.84 (d, 3H, CH₃) and 0.81 (d, 3H, CH₃).

[0931] (R)-4-((R)-1,2-Dimethyl-propyl)-dihydro-furan-2-one 180

[0932] To a solution of aromatic compound 179 (5.0 g, 20.16 mmol) inHPLC grade acetonitrile (60 mL), carbon tetrachloride (60 mL), and water(120 mL) was added sodium periodate (86.24 g, 403.32 mmol, 20 equiv.),followed by RuCl₃ (414 mg, 10 mol %). The mixture was stirred vigorouslyovernight at room temperature, and diluted with methylene chloride (400mL). The mixture was filtered through a pad of Celite to remove thesolid precipitate. The organic portion was separated, and the aqueouswas further extracted with methylene chloride. After the combinedorganic portions concentrated, the residue was dissolved in ether andapplied to a column of Florisil. The compound was eluted with 3%methanol in ether, evaporated to a paste that was dissolved in methanol(100 mL). Potassium carbonate (8.0 g) was added, and the mixture wasrefluxed for 6 hours. The solvent was evaporated, and the solid residuewas dissolved in water. The pH was adjusted to 2 by the careful additionof concentrated HCl while being cooled in ice water bath and stirred.Chloroform (200 mL) was added to the solution and stirred as suchovernight at room temperature. The organic phase was separated, and theaqueous portion was further extracted with chloroform. After drying, thesolvent was evaporated to give the lactone 180 5.0 g. NMR (CDCl₃) δ 4.36(app. t, 1H, CH_(a)HbO), 3.85 (app. t, 1H, CH_(a)HbO), 2.46 (m, 2H,CHCH_(d) C═O), 2.13 (m, 2H, CHCH₂C═O), 1.60 (m, 1H, CH(Me)₂), 1.35 (m,1H, CH₃CHCH(Me)₂), 0.86 (d, 3H, CH₃) and 0.72 (t, 3H, CH₃).

[0933] (3R,4R)-3-Bromomethyl-4,5-dimethyl-hexanoic Acid Ethyl Ester 181

[0934] Lactone 180 (5.0 g) was dissolved in absolute ethanol (25 mL) andflushed with argon. While being cooled in ice water bath, anhydrous HBrgas was bubbled through the mixture for 45 minutes and allowed to standat room temperature overnight. The mixture was poured into ice-saltwater and hexane. The organic phase was separated, and the aqueous wasfurther extracted with hexane. The combined organic extract was driedand evaporated. Flash chromatography with 10% ether in pet ether on asilica gel column gave the bromoester 181 3.54 g. NMR (CDCl₃) δ 4.14 (q,2H, CH₃H₂O), 3.60 (dd, 1H, CH_(a)H_(b)Br), 3.41 (dd, 1H, CH_(c)H_(b)Br),2.54 (dd, 1H, CH_(a)H_(b)C═O), 2.44 (dd, 1H, CH_(a)H_(b)C═O), 2.22 (m,1H, O═CCH₂CHCH₂Br), 1.67 (m, 1H, CHCH₃CH(Me)₂, 1.37 (m, 1H, CH(Me)₂),1.26 (t, 3H, CH₃CH₂O), 0.94 (d, 3H, CHCH₃CH(Me)₂, 0.81 (d, 3H,((CH₃)₂)CHCH₃CH) and 0.79 (d, 3H, ((CH₃)₂)CHCH₃CH).

[0935] (3R,4R)-3-Azidomethyl-4,5-dimethyl-hexanoic acid ethyl ester 182and Example 17 (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic Acid

[0936] Bromoester 181 (3.54 g, 13.34 mmol), sodium azide (1.04 g, 16.13mmol) in anhydrous DMF (8.0 mL) was stirred at room temperatureovernight. Water (16 mL) and hexane were added, the organic portion wasseparated, and the aqueous portion was further extracted with hexane. Itwas dried and evaporated to give azido ester 3.0 g. NMR (CDCl₃) δ 4.14(q, 2H, CH₃H₂O), 3.48 (dd, 1H, CH_(a)H_(b)N₃), 3.21 (dd, 1H,CH_(c)H_(b)N₃), 2.34 (m 2H, CH_(a)H_(b)C═O), 2.20 (m, 1H, O═CCH₂CHCH₂N₃), 1.60 (m, 1H, CHCH₃CH(Me)₂. Compound was submitted for hydrogenation(HPL, 66480×100). The hydrogenated crude was dissolved in 6N HCl andrefluxed overnight. The solvent was evaporated in vacuo the residue wasazeotroped with toluene. The crude was further purified by loading ontoan ion exchange column chromatography (Dowex 50Wb×8−100), washed toneutral eluent with HPLC grade water followed by elution of compoundwith 0.5N NH₄OH solution. Crystallization of product from methanol gave720 mg. NMR (CD₃OD) δ 3.04 (dd, 1H, CH_(a)H_(b)NH₂), 2.82 (dd, 1H,CH_(c)H_(b)NH₂), 2.52 (dd, 1H, CH_(a)H_(b)C═O), 2.40 (dd, 1H,CH_(a)H_(b)C═O), 2.07 (m, 1H, O═CCH₂CHCH₂NH₂), 1.67 (m, 1H,CHCH₃CH(Me)₂, 1.35 (m, 1H, CH(Me)₂), 0.97 (d, 3H, CHCH₃CH(Me)₂, 0.88 (d,3H, ((CH₃)₂)CHCH₃CH) and 0.83 (d, 3H, ((CH₃)₂)CHCH₃CH). [α]_(D)−5.3 (c,MeOH, 1.9 mg/mL). Anal. Calcd for C₉H₁₉NO₂: C, 62.39; H, 11.05; N, 8.08.Found C, 62.01; H, 11.35; N, 7.88.

[0937] MS showed ions at 215 (M+CH₃CN), 197 (M+Na⁺), 174 (M+H⁺).Analysis of derivative by reverse phase HPLC, Hypersil BDS C₁₈ 5 micronand mobile phase 50/50 CH₃CN-water containing 0.1% TFA gave 99.93%purity at retention time of 8.21 minutes.

Examples 18-20 Synthesis of 3-Aminomethyl-4-isopropyl-heptanoic Acid

[0938]

[0939] 2-Cyano-4-methyl-2-pentenoic acid methyl Ester 61

[0940] A solution of isobutyraldehyde (30.0 g, 416 mmol),methyl-cyano-acetate (20.6 g, 208 mmol), ammonium hydroxide (3.2 g, 41.6mmol) and acetic acid (5.0 g, 83.2 mmol) in 500 mL of toluene is warmedto reflux under a Dean-Stark trap for 12 hours. The mixture is cooled toroom temperature and extracted with saturated NaHSO₃ (3×100 mL),saturated NaHCO₃ (3×100 mL), and 100 mL of brine. The organic layer isdried over Na₂SO₄, and the solvent is evaporated. The remaining oil isdistilled under high vacuum (0.5 mm Hg, B.P. =115-120° C.) to give 28.8g of 2-cyano-4-methyl-2-pentenoic acid methyl ester 61 as an oil (90%yield).

[0941] 2-Cyano-3-isopropyl-hexanoic Acid Methyl Ester 183

[0942] A 2.0 M solution of propyl magnesium chloride in Et₂O (9.8 mL,19.6 mmol) is added to a solution of 2-cyano-4-methyl-2-pentenoic acid(3.0 g, 19.6 mmol) in 50 mL of THF which is cooled in an IPA/dry icebath to −40° C. under argon. The solution is stirred for 4 hours, andthe reaction is quenched by addition of 50 mL of saturated KH₂PO₄. TheTHF is evaporated, and the remaining oil is chromatographed under mediumpressure over silica gel with 50% CH₂Cl₂/hexane. Yield=1.9 g (50%) of2-cyano-3-isopropyl-hexanoic acid methyl ester as an oil.

[0943] 2-Cyano-2-(1-isopropyl-butyl)-succinic Acid 4-tert-butyl Ester1-methyl Ester 184

[0944] A solution of 2-cyano-3-isopropyl-hexanoic acid methyl ester (1.9g, 9.6 mmol) in 10 mL of THF is added to a slurry of NaH (washed withhexane, 0.23 g, 9.6 mmol) in 20 mL of THF which is cooled in an icewater bath under argon. The solution is stirred for 10 minutes, andt-butyl bromoacetate (2.1 g, 10.6 mmol) is added. The solution is warmedto room temperature. After 12 hours, the reaction is quenched byaddition of 50 mL of saturated KH₂PO₄ and the THF is evaporated. Theorganic products are extracted into Et₂O (3×50 m]L), and the combinedorganic layers are dried over MgSO₄. The solvent is evaporated, and theremaining oil is chromographed under medium pressure over silica gel in25% hexane/CH₂Cl₂. Yield of 2-cyano-2-(1-isopropyl-butyl)-succinic acid4-tert-butyl ester 1-methyl ester=1.3 g (42%) as an oil.

[0945] 3-Cyano-4-isopropyl-heptanoic Acid t-butyl Ester 185

[0946] A mixture of 2-cyano-2-(1-isopropyl-butyl)-succinic acid4-tert-butyl ester 1-methyl ester (1.3 g, 4.2 mmol), NaCl (0.25 g, 4.2mmol), and H₂O (0.15 g, 8.3 mmol) in 25 mL of DMSO is warmed to 130° C.for 12 hours. The mixture is cooled to room temperature and diluted with100 mL of brine. The organic products are extracted into Et2O (3×50 mL).The organic layers are combined and washed with 50 mL of H₂O and 50 mLof brine. Drying over Na₂SO₄ and evaporation of the solvent gives 0.8 g(75% yield) of 3-cyano-4-isopropyl-heptanoic acid t-butyl ester as anoil. 4-(1-Isopropyl-butyl)-2-pyrrolidone 1863-Cyano-4-isopropyl-heptanoic acid t-butyl ester (0.8 g, 3.2 mmol) isreduced under 50 psi of H₂ in MeOH containing TEA and Ra Ni. When thetheoretical amount of H₂ is taken up, the catalyst is removed byfiltration, and the solvent is evaporated to give 0.6 g (100% yield) of4-(1-isopropyl-butyl)-2-pyrrolidone as an oil.

Example 18 3-Aminomethyl-4-isopropyl-heptanoic Acid

[0947] 4-(1-Isopropyl-butyl)-2-pyrrolidone (0.6 g, 2.3 mmol) is warmedto reflux in 50 mL of 6.0 M HCl for 12 hours. The solution is cooled toroom temperature and filtered through Celite. The filtrate isevaporated, and the solid remaining is recrystallized from MeOH/EtOAc.Yield 0.035 g (6% yield) of 3-aminomethyl-4-isopropyl-heptanoic acid asan HCl salt, mp 160-170° C. ¹H NMR (CD₃OD) δ 0.9 (m, 9H), 1.30 (m, 5H),1.78 (m, 1H), 2.30 (m, 2H), 2.45 (m, 1H), 2.95 (m, 2H). MS (APCI, CH₃CN,H₂O) 201 (M+, 100%).

Example 19 3-Aminomethyl-4-isopropyl-octanoic Acid

[0948] Prepared according to the procedure of Example 18. Yield=0.13 g(15%) of 3-aminomethyl-4-isopropyl-octanoic acid. mp=160-170° C. ¹H NMR(CD₃OD) δ 0.9 (m, 9H), 1.30 (m, 7H), 1.78 (m, 1H), 2.30 (m, 1H), 2.45(m, 2H), 2.95 (m, 2H). MS (APC₁, CH₃CN, H₂O) 198 (M−17, 100%), 216 (M+,50%).

Example 20 3-Aminomethyl-4-isopropyl-hexanoic Acid

[0949] Prepared according to the procedure of Example 18. Yield=0.11 g(42%) of 3-aminomethyl-4-isopropyl-hexanoic acid. mp=170-180° C. ¹H NMR(CD₃OD) δ 0.9 (m, 9H), 1.18 (m, 1H), 1.39 (m, 3H), 1.78 (m, 1H), 2.30(m, 1H), 2.45 (m, 1H), 2.95 (m, 2H). MS (APCI, CH₃CN, H₂O) 188 (M⁺,100%).

EXAMPLE 21

[0950]

[0951] Synthesis of the Unsaturated Ester 188

[0952] (S)-(−)-citronellal 187 (2.0 mL, 11.03 mmol) was stirred at 40°C. in dry tetrahydrofuran (30 mL) with methyl triphenylphosphoranylideneacetate (3.69 g, 11.03 mmol). After 8 hours the mixture was cooled toroom temperature and stirred overnight. The solvent was removed in vacuoand the residue stirred with n-pentane (50 mL). After 1 hour the solidwas removed by filtration and the solvent removed in vacuo to give anoil which was purified by flash chromatography (silica, ethylacetate:heptane 1:9) to give 2.05 g (88%) of 188 as a clear oil. ¹H NMR(400 MHz) (CDCl₃) δ 0.90 (3H, d, J=6 Hz); 1.12-1.40 (2H, m); 1.60 (3H,s); 1.62 (1H, m); 1.68 (3H, s); 2.01 (3H, m); 2.21 (1H, m); 3.73 (3H,s); 5.08 (1H, m); 5.82 (1H, d, J=16 Hz); 6.94 (1H, m). MS (CI⁺) (m/z):211 (MH⁺, 75%), 179 (78%), 151 (100%). IR (thin film) (cm⁻¹) v: 1271,1436, 1728, 2917.

[0953] Synthesis of the Nitroester 189

[0954] The ester 188 (2.02 g, 9.6 mmol) was dissolved in nitromethane(25 mL) with 1,8-diazabicyclo[5,4,O]undec-7-ene (1.44 mL, 9.6 mmol) andstirred at room temperature. After 23 hours the mixture was diluted withdiethyl ether (150 mL) and washed with water (50 mL) and then 2N HCl (50mL). The organic phase was collected, dried (MgSO₄), and the solventremoved in vacuo. The residue was purified by flash chromatography(silica, ethyl acetate:heptane 3:7) to give 2.26 g (87%) of 189 as aclear oil. Note that this and all subsequent compounds are equimolarmixtures of 2 diastereoisomers. ¹H NMR (400 MHz) (CDCl₃) δ 0.90 (2×3H,each d, J=6 Hz); 1.09-1.58 (10H, m); 1.602 (6H, s); 1.685 (6H, s); 1.94(4H, m); 2.42 (4H, m); 2.66 (2H, m); 3.70 (6H, s); 4.42 (4H, m); 5.07(2H, m).

[0955] MS (CI⁺) (m/z): 272 (MH⁺, 90%), 240 (100%), 151 (100%).

[0956] IR (thin film) (cm⁻¹) υ: 1554, 1739, 2918.

[0957] Synthesis of the Lactam 191

[0958] The nitro ester 189 (2.09 g, 7.7 mmol) was dissolved in methanol(75 mL) and shaken over Raney Nickel (catalytic, prewashed with waterand then methanol) under an atmosphere of hydrogen gas (39 psi) at 35°C. After 17 hours the mixture was filtered through Celite. The solventwas removed in vacuo to give an oil. ¹H NMR showed there had beenpartial reduction of the double bond so this was carried on withoutfurther purification. A sample of this partial reduced product (440 mg,2.1 mmol) was dissolved in methanol (40 mL) and shaken over 5% Pd—Cunder an atmosphere of hydrogen gas. After 18 hours the catalyst wasremoved by filtration through Celite to obtain 442 mg (99% from partialreduced material) as a clear oil which did not need purification. Notethat this and all subsequent compounds are equimolar mixtures of 2diastereoisomers. ¹H NMR (400 MHz) (CDCl₃) δ: 0.88 (18H, m); 1.04-1.58(20H, m); 1.96 (2H, m); 2.40 (2H, m); 2.58 (2H, m); 2.98 (2H, m); (3.45(2H, m), 5.82 (2H, br s). MS (CI⁺) (m/z): 212 (MH⁺, 100%).

Synthesis of Example 21

[0959] The lactam 191 (428 mg, 2.0 mmol) was heated to reflux in 6N HCl(20 mL). After 5 hours the mixture was cooled to room temperature andwashed with dichloromethane (2×10 mL). The aqueous phase was collectedand the solvent removed in vacuo. The residue was dissolved in water (10mL) and freeze-dried to give 382 mg (71%) of Example 34 as a whitesolid. Note that this compound is an equimolar mixture of 2diastereoisomers. ¹H NMR (400 MHz) (d₆-DMSO) δ 0.82 (18H, m); 0.95-1.55(20H, m); 2.05-2.45 (6H, m); 2.75 (4H, m); 7.98 (6H, br s).

[0960] MS (CI⁺) (m/z): 230 ([MH—HCl]⁺, 90%), 212 (100%).

[0961] Microanalysis: Calculated for C₁₃H₂₈NO₂Cl: C 58.74; H 10.62; N5.27.

[0962] Found: C 58.46; H 10.50; N 5.33.

[0963] To one skilled in the art, the use of (R)-(+)-citronellal wouldafford compounds of opposite C5-stereochemistry to Example 21.

1. A method for treating restless leg syndrome comprising administeringa therapeutically effective amount of a compound according to formula I:

or a pharmaceutically acceptable salt thereof to a mammal in need ofsaid treatment wherein: R¹ is hydrogen, straight or branched alkyl offrom 1 to 6 carbon atoms or phenyl; R² is straight or branched alkyl offrom 4 to 8 carbon atoms, straight or branched alkenyl of from 2 to 8carbon atoms, cycloalkyl of from 3 to 7 carbon atoms, alkoxy of from 1to 6 carbon atoms, alkylcycloalkyl, alkylalkoxy, alkyl OH, alkylphenyl,alkylphenoxy, and substituted phenyl.
 2. The method according to claim 1wherein R¹ is hydrogen and R² is straight or branched alkyl of from 4 to8 carbon atoms.
 3. The method according to claim 1 wherein R² issubstituted phenyl, or alkylphenyl.
 4. The method according to claim 1wherein R² is alkylphenoxy.
 5. The method according to claim 1 whereinR² is cycloalkyl or alkylcycloalkyl.
 6. The method according to claim 1wherein R² is alkylhydroxy.
 7. The method according to claim 1 whereinsaid compound is selected from: 3-Aminomethyl-5-methyl-nonanoic acid;3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-methyl-undecanoicacid; 3-Aminomethyl-5-methyl-dodecanoic acid;3-Aminomethyl-5-methyl-tridecanoic acid;3-Aminomethyl-5-cyclopropyl-hexanoic acid;3-Aminomethyl-5-cyclobutyl-hexanoic acid;3-Aminomethyl-5-trifluoromethyl-hexanoic acid;3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid;3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid;3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid;3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid;3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid;3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and3-Aminomethyl-5-(phenylmethyl)-hexanoic acid.
 8. A method for treatingrestless leg syndrome comprising administering a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable saltthereof to a mammal in need of said treatment wherein said compound is(3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid.
 9. A method for treatingrestless leg syndrome comprising administering a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable saltthereof to a mammal in need of said treatment wherein said compound is(3S,5R)-3-Aminomethyl-5-methyl-octanoic acid.
 10. The method accordingto claim 1 wherein said compound is(3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid.
 11. The method accordingto claim 1 wherein said compound is(3S,5R)-3-Aminomethyl-5-methyl-decanoic acid.
 12. The method accordingto claim 1 wherein said compound is(3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid.
 13. The method accordingto claim 1 wherein said compound is(3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid.
 14. The method accordingto claim 1 wherein said compound is selected from:(3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid;(3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid;(3S,5R)-3-Aminomethyl-5, 10-dimethyl-undecanoic acid;(3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;(3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;(3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;(3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;(3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;(3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;(3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;(3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;(3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; and(3S,5R)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid.
 15. The methodaccording to claim 1 wherein said compound is selected from:(3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoicacid; (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoicacid; (3S,5S)-3-Aminomethyl-5-methyl6-(3-trifluoromethyl-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoicacid; (3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid;(3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;(3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoicacid; (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7-(2-methoxy-phenoxy)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoicacid;(3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoicacid;(3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoicacid; (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid;(3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-hept-6-enoic acid;(3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid;(3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid;(E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;(Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;(Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;(E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;(E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;(Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;(Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid;(E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid;(3S,5S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;(3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid;(3S,5S)-3-Aminomethyl-5-cyclobutyl-hexanoic acid;(3S,5R)-3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;(3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; and(3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid.
 16. A method fortreating restless leg syndrome comprising administering atherapeutically effective amount of a compound or a pharmaceuticallyacceptable salt thereof to a mammal in need of said treatment whereinsaid compound is selected from: 3-Aminomethyl-5-methylheptanoic acid;3-Aminomethyl-5-methyl-octanoic acid;3-Aminomethyl-4,5-dimethyl-hexanoic acid;(3S,4S)3-Aminomethyl-4,5-dimethyl-hexanoic acid;(3R,4R)3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;3-Aminomethyl-4-isopropyl-hexanoic acid;3-Aminomethyl-4-isopropyl-heptanoic acid;(3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;(3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;(3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid;(3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid;(3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid;(3R,4R,5R)-3-Aminomethyl-4,5-dimethyl-heptanoic acid; and(3R,4R,5R)-3-Aminomethyl-4,5-dimethyl-octanoic acid.